Method for the preparation of tetrahydrobenzothiepines

ABSTRACT

Among its several embodiments, the present invention provides an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to the preparation of apical sodiumco-dependent bile acid transporter (ASBT) inhibitors and moreparticularly to the preparation of benzothiepine ASBT inhibitors. Thisinvention especially relates to methods of preparingtetrahydrobenzothiepine oxide ASBT inhibitors.

[0003] 2. Description of Related Art

[0004] It is well established that agents which inhibit the transport ofbile acids across the tissue of the ileum can also cause a decrease inthe levels of cholesterol in blood serum. Stedronski, in “Interaction ofbile acids and cholesterol with nonsystemic agents havinghypocholesterolemic properties,” Biochirnica et Biophysica Acta, 1210(1994) 255-287 discusses biochemistry, physiology, and known activeagents surrounding bile acids and cholesterol. Bile acids are activelytransported across the tissue of the ileum by an apical sodiumco-dependent bile acid transporter (ASBT), alternatively known as anileal bile acid transporter (IBAT).

[0005] A class of ASBT-inhibiting compounds that was recently discoveredto be useful for influencing the level of blood serum cholesterolcomprises tetrahydrobenzothiepine oxides (THBO compounds, PCT PatentApplication No. WO 96/08484). Further THBO compounds useful as ASBTinhibitors are described in PCT Patent Application No. WO 97/33882.Additional THBO compounds useful as ASBT inhibitors are described inU.S. Pat. No. 5,994,391. Still further THBO compounds useful as ASBTinhibitors are described in PCT Patent Application No. WO 99/64409.Included in the THBO class are tetrahydrobenzo thiepine-1-oxides andtetrahydrobenzothiepine-1,1-dioxides. THBO compounds possess chemicalstructures in which a phenyl ring is fused to a seven-member ring.

[0006] Published methods for the preparation of THBO compounds includethe synthesis through an aromatic sulfone aldehyde intermediate. Forexample1-(2,2-dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene(29) was cyclized with potassium t-butoxide to formtetrahydrobenzothiepine-1,1-dioxide (syn-24) as shown in Eq. 1.

[0007] Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acidchloride with anisole in the presence of aluminum trichloride to producea chlorobenzophenone compound; the chlorobenzophenone compound wasreduced in the presence of trifluoromethanesulfonic acid andtriethylsilane to produce a chlorodiphenylmethane compound; thechlorodiphenylmethane compound was treated with lithium sulfide and2,2-dibutyl-3-(methanesulfonato)propanal to produce1-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene(40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29.The first step of that method of preparing compound 29 requires the useof a corrosive and reactive carboxylic acid chloride that was preparedby the reaction of the corresponding carboxylic acid with phosphoruspentachloride. Phosphorus pentachloride readily hydrolyzes to producevolatile and hazardous hydrogen chloride. The reaction of2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide andthe chlorodiphenylmethane compound required the intermediacy of a cyclictin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal.The tin compound is expensive and creates a toxic waste stream.

[0008] In WO 97/33882 compound svn-24 was dealkylated using borontribromide to produce the phenol compound 28. Boron tribromide is acorrosive and hazardous material that generates hydrogen bromide gas andrequires special handling. Upon hydrolysis, boron tribromide alsoproduces borate salts that are costly and time-consuming to separate anddispose of.

[0009] An alternative method of preparing THBO compounds was describedin WO 97/33882, wherein a 1,3-propanediol was reacted with thionylchloride to form a cyclic sulfite compound. The cyclic sulfite compoundwas oxidized to produce a cyclic sulfate compound. The cyclic sulfatewas condensed with a 2-methylthiophenol that had been deprotonated withsodium hydride. The product of the condensation was a (2-methylphenyl)(3′-hydroxypropyl)thioether compound. The thioether compound wasoxidized to form an thioether aldehyde compound. The thioether aldehydecompound was further oxidized to form an aldehyde sulfone compound whichin turn was cyclized in the presence of potassium t-butoxide to form a4-hydroxytetrahydrobenzothiepine 1,1-dioxide compound. This cyclicsulfate route to THBO compounds requires an expensive catalyst.Additionally it requires the use of SOCl₂, which in turn requiresspecial equipment to handle.

[0010] PCT Patent Application No. WO 97/33882 describes a method bywhich the phenol compound 28 was reacted at its phenol hydroxyl group toattach a variety of functional groups to the molecule, such as aquaternary ammonium group. For example, (4R,5R)-28 was reacted with1,4-bis(chloromethyl)benzene (?,??′-dichloro-p-xylene) to produce thechloromethyl benzyl ether (4R,5R)-27. Compound (4R,5R)-27 was treatedwith diazabicyclo[2.2.2]octane (DABCO) to produce(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octanechloride (41). This method suffers from low yields because of apropensity for two molecules of compound (4R,5R)-28 to react with onemolecule of 1.4-bis(chloromethyl)benzene to form a bis(benzothiepine)adduct. Once the bis-adduct forms the reactive chloromethyl group ofcompound (4R,5R)-27 is not available to react with an amine to form thequaternary ammonium product.

[0011] A method of preparing enantiomerically enrichedtetrahydrobenzothiepine oxides is described in PCT Patent ApplicationNo. WO 99/32478. In that method, an aryl-3-hydroxypropylsulfide compoundwas oxidized with an asymmetric oxidizing agent, for example(1R)-(−)-(8,9-dichloro-10-camphorsulfonyl)oxaziridine, to yield a chiralaryl-3-hydroxypropylsulfoxide. Reaction of thearyl-3-hydroxypropylsulfoxide with an oxidizing agent such as sulfurtrioxide pyridine complex yielded an aryl-3-propanalsulfoxide. Thearyl-3-propanalsulfoxide was cyclized with a base such as potassiumt-butoxide to enantioselectively produce atetrahydrobenzothiepine-1-oxide. The tetrahydrobenzothiepine-1-oxide wasfurther oxidized to produce a tetrahydrobenzothiepine-1,1-dioxide.Although this method could produce tetrahydrobenzothiepine-1,1-dioxidecompounds of high enantiomeric purity, it requires the use of anexpensive asymmetric oxidizing agent.

[0012] Some 5-amidobenzothiepine compounds and methods to make them aredescribed in PCT Patent Application Number WO 92/18462.

[0013] In Synlett, 9, 943-944(1995) 2-bromophenyl3-benzoyloxy-1-buten-4-yl sulfone was treated with tributyl tin hydrideand AIBN to produce 3-benzoyloxytetrahydrobenzothiepine-1,1-dioxide.

SUMMARY OF THE INVENTION

[0014] The ongoing work in the area of tetrahydrobenzothiepine synthesisand the utility of 4-hydroxy-5-phenyltetrahydrobenzothiepine-1,1-dioxidecompounds as cholesterol-lowering therapeutics point to the continuingneed for economical and practical methods to prepare these compounds.

[0015] We now report a novel method for preparingtetrahydrobenzothiepine compounds. Among the several embodiments of thepresent invention may be noted the provision of an improved process forthe preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; theprovision of a process for preparing a diastereomeric mixture oftetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomerof such compounds; the provision of a process for the preparation of3-bromo-2-substituted propionaldehyde compounds; and the provision of aprocess for the preparation of 3-thio-2-substituted propionaldehydecompounds.

[0016] Briefly, therefore, the present invention is directed to a methodfor the preparation of a benzylammonium compound having the structure ofFormula 60

[0017] wherein the method comprises treating a benzyl alcohol ethercompound having the structure of Formula 61

[0018] under derivatization conditions to form a derivatized benzylether compound having the structure of Formula 62

[0019] and contacting the derivatized benzyl ether compound with anamine having the structure of Formula 42

[0020] under amination conditions thereby producing the benzylammoniumcompound or a derivative thereof, wherein:

[0021] R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl;

[0022] R³, R⁴, and R⁵ independently are selected from the groupconsisting of H and C₁ to about C₂₀ hydrocarbyl, wherein optionally oneor more carbon atom of the hydrocarbyl is replaced by O, N, or S, andwherein optionally two or more of R³, R⁴, and R⁵ taken together with theatom to which they are attached form a cyclic structure;

[0023] R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³, R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

[0024] R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M;

[0025] n is a number from 0 to 4;

[0026] A⁻ is a pharmaceutically acceptable anion and M is apharmaceutically acceptable cation; and

[0027] X is a nucleophilic substitution leaving group.

[0028] The present invention is also directed to a method for thepreparation of a benzylammonium compound having the structure of Formula1

[0029] wherein the method comprises treating a benzyl alcohol ethercompound having the structure of Formula 6

[0030] under derivatization conditions to form a derivatized benzylether compound having the structure of Formula 2

[0031] and contacting the derivatized benzyl ether compound with anamine having the structure of Formula 42:

[0032] under amination conditions thereby producing the benzylammoniumcompound or a derivative thereof, wherein R¹, R², R³, R⁴, R⁵, and X aredefined above.

[0033] The invention is further directed to a method for the preparationof a benzylammonium compound having the structure of Formula 1 whereinthe method comprises the steps of: treating a protected phenol compoundhaving the structure of Formula 14

[0034] with a substituted benzoyl compound having the structure ofFormula 15

[0035] under acylation conditions to produce a substituted benzophenonecompound having the structure of Formula 13

[0036] reducing the substituted benzophenone compound to produce asubstituted diphenyl methane compound having the structure of Formula 11

[0037] coupling the substituted diphenyl methane compound with asubstituted propionaldehyde compound having the structure of Formula 12

[0038] in the presence of a source of sulfur to form a nitro sulfidealdehyde compound having the structure of Formula 10

[0039] oxidizing the nitro sulfide aldehyde compound to form a nitrosulfone aldehyde compound having the structure of Formula 9

[0040] reductively alkylating the nitro sulfone aldehyde compound toform an amino sulfone aldehyde compound having the structure of Formula8

[0041] treating the amino sulfone aldehyde compound under cyclizationconditions to form protected phenol compound having the structure ofFormula 7

[0042] deprotecting the protected phenol compound to form a phenolcompound having the structure of Formula 4

[0043] coupling the phenol compound with a substituted xylene having thestructure of Formula 5

[0044] under substitution conditions to produce a benzyl alcohol ethercompound having the structure of Formula 6 treating the benzyl alcoholether compound under derivatization conditions to produce a derivatizedbenzyl ether compound having the structure of Formula 2; and treatingthe derivatized benzyl ether compound with an amine having the structureof Formula 42 under amination conditions to produce the benzylammoniumcompound 1; wherein: R¹, R², R³, R⁴, and R⁵ are as defined above; R6 isa protecting group, X and X⁴ independently are nucleophilic substitutionleaving groups, X² is selected from the group consisting of chloro,bromo, iodo, methanesulfonato, toluenesulfonato, benzenesulfonato, andtrifluoromethanesulfonato; X³ is an aromatic substitution leaving group;and X⁵ is selected from the group consisting of hydroxy and halo.

[0045] The present invention is also directed to a method for thepreparation of a benzylammonium compound having the structure of Formula1 wherein the method comprises a step in which an acetal compound havingthe structure of Formula 18

[0046] is thermolyzed to form an alkenyl sulfone aldehyde compoundhaving the structure of Formula 16

[0047] wherein R¹ and R⁶ are as defined above; R⁷ is selected from thegroup consisting of H and C₁ to about C₁₇ hydrocarbyl; and R¹³ isselected from the group consisting of H and C₁ to about C₂₀ hydrocarbyl.

[0048] In another embodiment, the present invention is directed to amethod of treating a diastereomer of a tetrahydrobenzothiepine compoundhaving the structure of Formula 22

[0049] wherein Formula 22 comprises a (4,5)-diastereomer selected fromthe group consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer,a (4R,5S) diastereomer, and a (4S,5R) diastereomer, to produce a mixturecomprising the (4S,5S) diastereomer and the (4R,5R) diastereomer,wherein the method comprises contacting a base with a feedstockcomposition comprising the diastereomer of the tetrahydrobenzothiepinecompound, thereby producing a mixture of diastereomers of thetetrahydrobenzothiepine compound; and wherein:

[0050] R⁸ is selected from the group consisting of H, hydrocarbyl,heterocycle, ((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl,((heterocycloalkyl)alkylaryl)alkyl, ((quaternaryheterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl,

[0051] wherein hydrocarbyl, heterocycle, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, and quaternary heteroarylalkyloptionally have one or more carbons replaced by a moiety selected fromthe group consisting of O, NR³, N⁺R³R⁴A⁻, S, SO, SO₂, S⁺R³A⁻, P⁺R³,P⁺R³R⁴A⁻, P(O)R³, phenylene, carbohydrate, amino acid, peptide, andpolypeptide, and

[0052] R⁸ is optionally substituted with one or more moieties selectedfrom the group consisting of sulfoalkyl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N^(+l R) ³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴,P⁺R³R⁴R⁵A⁻, S⁺R⁺R⁴A⁻, and C(O)OM;

[0053] R¹, R², R³, R⁴, R⁵, R⁹, R²³ and R²⁴, n, A⁻, and M are as definedabove;

[0054] X⁷ is S, NH, or O; and

[0055] x is 1 or 2.

[0056] In yet another embodiment, the present invention is directed to amethod of treating a diastereomer of a tetrahydrobenzothiepine compoundhaving the structure of Formula (22), wherein the method comprisestreating the diastereomer of the tetrahydrobenzothiepine compound underelimination conditions to produce a dihydrobenzothiepine compound havingthe structure of Formula 23

[0057] and oxidizing the dihydrobenzothiepine compound to produce themixture of diastereomers, wherein:

[0058] R¹, R², R⁸, R⁹, X⁷, and n are as defined above; and

[0059] x is 0, 1, or 2.

[0060] Another embodiment of the present invention is directed to amethod for the preparation of a substituted propionaldehyde compoundhaving the structure of Formula 12 wherein the method comprisesoxidizing a substituted propanol compound having the structure ofFormula 35

[0061] wherein R¹ and R² are as defined above, and X⁴ is a nucleophilicsubstitution leaving group.

[0062] In another embodiment, the present invention is directed toward acompound having the structure of Formula (2) wherein R¹ and R²independently are C₁ to about C₂₀ hydrocarbyl and X is selected from thegroup consisting of Br, I, and a nucleophilic substitution leaving groupcovalently bonded to the compound via an oxygen atom.

[0063] In another embodiment, the present invention provides acrystalline form of a tetrahydrobenzothiepine compound having thestructure of Formula 71

[0064] or an enantiomer thereof wherein the crystalline form has amelting point or a decomposition point of about 278° C. to about 285° C.

[0065] Another embodiment of the present invention provides acrystalline form of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71 andwhich after a sample of the crystalline form is dried at essentially 0%relative humidity at about 25° C. under a purge of essentially drynitrogen until the sample exhibits essentially no weight change as afunction of time, the sample gains less than 1% of its own weight whenequilibrated under about 80% relative humidity air at about 25° C.Preferably the crystal form of the present invention comprises a(4R,5R)-enantiomer of compound 71.

[0066] Still another embodiment of the present invention provides acrystalline form of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71 or anenantiomer thereof and wherein the crystalline form is produced bycrystallizing the tetrahydrobenzothiepine compound from a solventcomprising methyl ethyl ketone. Preferably the crystal form of thepresent invention comprises a (4R,5R)-enantiomer of compound 71.

[0067] In another embodiment, the present invention provides a methodfor the preparation of a crystalline form of a tetrahydrobenzothiepinecompound having the structure of Formula 63

[0068] wherein the method comprises crystallizing thetetrahydrobenzothiepine compound from a solvent comprising a ketone (forexample methyl ethyl ketone or acetone, preferably methyl ethyl ketone),and wherein R¹, R², R³, R⁴, R⁵, R⁹, and n are defined above. In Formula63 Q⁻ is a pharmaceutically acceptable anion.

[0069] In another embodiment, the present invention provides a methodfor the preparation of a product crystal form of atetrahydrobenzothiepine compound having the compound structure ofFormula 41 wherein the product crystal form has a melting point or adecomposition point of about 278° C. to about 285° C., wherein themethod comprises applying heat to an initial crystal form of thetetrahydrobenzothiepine compound wherein the initial crystal form has amelting point or a decomposition point of about 220° C. to about 235°C., thereby forming the product crystal form.

[0070] Further scope of the applicability of the present invention willbecome apparent from the detailed description provided below. However,it should be understood that the following detailed description andexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

[0071]FIG. 1 shows an overall process by which substitutedpropionaidehyde compound 12 can be prepared.

[0072]FIG. 1a shows a representative overall process by which nitrosulfide acetal compound 67 can be prepared and by which compound 67 canbe used to produce compound 29.

[0073]FIG. 2 shows a process by which 2,2-dibutyl-3-bromopropionaldehydecan be prepared using the methods of the present invention.

[0074]FIG. 3 shows an overall process for the preparation ofbenzylammonium compound 1.

[0075]FIG. 4 shows an overall process for the preparation of diphenylmethane compound 11.

[0076]FIG. 5 shows a method in which an enantiomerically enrichedtetrahydrobenzothiepine oxide 24 (for example (4R,5R)-24) can be used incombination with the methods of the present invention to prepare anenantiomerically enriched benzylammonium compound.

[0077]FIG. 6 shows representative X-ray powder diffraction patterns forForm I (plot (a)) and Form II (plot (b)) of compound 41. Horizontal axisvalues are in degrees 2 theta.

[0078]FIG. 7 shows representative Fourier transform infrared (FTIR)spectra for Form I (plot (a)) and Form II (plot (b)) of compound 41.Horizontal axis values are in cm⁻¹.

[0079]FIG. 8 shows representative solid state carbon-13 nuclear magneticresonance (NMR) spectra for Form I (plot (a)) and Form II (plot (b)) ofcompound 41. Horizontal axis values are in ppm.

[0080]FIG. 9 shows representative differential scanning calorimetryprofiles for Form I (plot (a)) and Form II (plot (b)) of compound 41.

[0081]FIG. 10 shows water sorption isotherms for Form I (plot (a)) andForm II (plot(b)) of compound 41.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0082] The following detailed description is provided to aid thoseskilled in the art in practicing the present invention. Even so, thisdetailed description should not be construed to unduly limit the presentinvention as modifications and variations in the embodiments discussedherein can be made by those of ordinary skill in the art withoutdeparting from the spirit or scope of the present inventive discovery.

[0083] The contents of each of the references cited herein, includingthe contents of the references cited within these primary references,are herein incorporated by reference in their entirety.

[0084] a. Definitions

[0085] The following definitions are provided in order to aid the readerin understanding the detailed description of the present invention:

[0086] “Hydrocarbyl” means an organic chemical group composed of carbonand hydrogen atoms. Without meaning to limit its definition, the termhydrocarbyl includes alkyl, alkenyl, alkynyl, aryl, cycloalkyl,arylalkyl, alkylarylalkyl, carbocycle, and polyalkyl.

[0087] “Alkyl,” “alkenyl,” and “alkynyl” unless otherwise noted are eachstraight chain or branched chain hydrocarbon groups of from one to abouttwenty carbons for alkyl or two to about twenty carbons for alkenyl andalkynyl in the present invention and therefore mean, for example,methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl,butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl,or hexynyl respectively and isomers thereof.

[0088] “Aryl” means a fully unsaturated mono- or multi-ring carbocycle,including, but not limited to, substituted or unsubstituted phenyl,naphthyl, or anthracenyl.

[0089] “Heterocycle” means a saturated or unsaturated mono- ormulti-ring carbocycle wherein one or more carbon atoms can be replacedby N, S, P, or O. This includes, for example, the following structures:

[0090] wherein Z, Z¹, Z² or Z³ is C, S, P, O, or N, with the provisothat one of Z, Z¹, Z² or Z³ is other than carbon, but is not O or S whenattached to another Z atom by a double bond or when attached to anotherO or S atom. Furthermore, the optional substituents are understood to beattached to Z, Z¹, Z² or Z³ only when each is C.

[0091] The term “heteroaryl” means a fully unsaturated heterocycle.

[0092] In either “heterocycle” or “heteroaryl,” the point of attachmentto the molecule of interest can be at the heteroatom or elsewhere withinthe ring.

[0093] The term “quaternary heterocycle” means a heterocycle in which atleast one heteroatom, for example, O, N, S, or P, has such a number ofbonds that the heteroatom is positively charged. The point of attachmentof the quaternary heterocycle to the molecule of interest can be at aheteroatom or elsewhere.

[0094] The term “quaternary heteroaryl” means a heteroaryl in which atleast one heteroatom, for example, O, N, S, or P, has such a number ofbonds that the heteroatom is positively charged. The point of attachmentof the quaternary heteroaryl to the molecule of interest can be at aheteroatom or elsewhere.

[0095] The term “halogen” means a fluoro, chloro, bromo or iodo group.

[0096] The term “haloalkyl” means alkyl substituted with one or morehalogens.

[0097] The term “cycloalkyl” means a mono- or multi-ringed carbocyclewherein each ring contains three to ten carbon atoms, and wherein anyring can contain one or more double or triple bonds. Examples includeradicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloalkenyl, and cycloheptyl. The term “cycloalkyl” additionallyencompasses spiro systems wherein the cycloalkyl ring has a carbon ringatom in common with the seven-membered heterocyclic ring of thebenzothiepine.

[0098] The term “oxo” means a doubly bonded oxygen.

[0099] The term “polyalkyl” means a branched or straight hydrocarbonchain having a molecular weight up to about 20,000, more preferably upto about 10,000, most preferably up to about 5,000.

[0100] The term “arylalkyl” means an aryl-substituted alkyl radical suchas benzyl. The term “alkylarylalkyl” means an arylalkyl radical that issubstituted on the aryl group with one or more alkyl groups.

[0101] The term “heterocyclylalkyl” means an alkyl radical that issubstituted with one or more heterocycle groups. Preferableheterocyclylalkyl radicals are “lower heterocyclylalkyl” radicals havingone or more heterocycle groups attached to an alkyl radical having oneto ten carbon atoms.

[0102] The term “heteroarylalkyl” means an alkyl radical that issubstituted with one or more heteroaryl groups. Preferableheteroarylalkyl radicals are “lower heteroarylalkyl” radicals having oneor more heteroaryl groups attached to an alkyl radical having one to tencarbon atoms.

[0103] The term “quaternary heterocyclylalkyl” means an alkyl radicalthat is substituted with one or more quaternary heterocycle groups.Preferable quaternary heterocyclylalkyl radicals are “lower quaternaryheterocyclylalkyl” radicals having one or more quaternary heterocyclegroups attached to an alkyl radical having one to ten carbon atoms.

[0104] The term “quaternary heteroarylalkyl” means an alkyl radical thatis substituted with one or more quaternary heteroaryl groups. Preferablequaternary heteroarylalkyl radicals are “lower quaternaryheteroarylalkyl” radicals having one or more quaternary heteroarylgroups attached to an alkyl radical having one to ten carbon atoms.

[0105] The term “alkoxy” means a radical comprising an alkyl radicalthat is bonded to an oxygen atom, such as a methoxy radical. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to tencarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, isopropoxy, butoxy and tert-butoxy.

[0106] The term “carboxy” means the carboxy group, —CO₂H, or its salts.

[0107] The term “carboalkoxyalkyl” means an alkyl radical that issubstituted with one or more alkoxycarbonyl groups. Preferablecarboalkoxyalkyl radicals are “lower carboalkoxyalkyl” radicals havingone or more alkoxycarbonyl groups attached to an alkyl radical havingone to six carbon atoms.

[0108] When used in combination, for example “alkylaryl” or “arylalkyl.”the individual terms listed above have the meaning indicated above.

[0109] As used herein, Me means methyl; Et means ethyl; Pr means propyl;i-Pr or Pr^(i) each means isopropyl; Bu means butyl; t-Bu or But eachmeans tert-butyl; Py means pyridine.

[0110] The term “derivative” means a compound containing a structuralmoiety similar to that of another chemical. The term derivativeincludes, for example, a conjugate acid, a conjugate base, a free base,a free acid, a racemate, a salt, an ester, a compound protected with aprotecting group, a tautomer, a stereoisomer, a substituted compound,and a prodrug.

[0111] The term “stereoisomer,” where a compound has at least one chiralcenter, includes each enantiomer and each diastereomer. Where a compoundhas an aliphatic double bond, the term “stereoisomer” includes each cisor Z isomer as well as each trans or E isomer.

[0112] In structural drawings, when a chemical bond is represented as anopen wedge, such a representation means that the bond can either go intothe plane of the page or come out of the plane of the page. When in astructural drawing two or more bonds are represented in the drawing asopen wedges (e.g., the structure of Formula 1 the bonds so indicated arein a syn conformation; that is to say all such bonds go into the planeof the page or all such bonds come out of the plane of the page.

[0113] In structural drawings, when a chemical bond is represented as afilled-in blackened wedge, such a representation means that the bond iscoming out of the plane of the page and represents a specificstereochemistry.

[0114] In structural drawings, when a chemical bond is represented as adashed wedge (e.g., the structure of compound 41), such a representationmeans that the bond is going into the plane of the page and represents aspecific stereochemistry.

[0115] In structural drawings, when a chemical bond is represented as awavy line (e.g., the structure of compound 24), such a representationmeans that the bond can assume any stereochemistry and can be syn, anti,cis, or trans with any of its neighboring bonds.

[0116] b. Process Details

[0117] In accordance with the present invention, a process has beendiscovered for economically preparing a benzylammonium compound havingthe structure of Formula 1 wherein the method comprises treating abenzyl alcohol ether compound having the structure of Formula 6 underderivatization conditions to form a derivatized benzyl ether compoundhaving the structure of Formula 2 and contacting the derivatized benzylether compound with an amine having the structure of Formula 42 underamination conditions thereby producing the benzylammonium compound or aderivative thereof, wherein: R¹ and R² independently are C₁ to about C₂₀hydrocarbyl; R³, R⁴, and R⁵ independently are selected from the groupconsisting of H and C₁ to about C₂₀ hydrocarbyl, wherein optionally oneor more carbon atom of the hydrocarbyl is replaced by O, N, or S, andwherein optionally two or more of R³, R⁴, and R⁵ taken together with theatom to which they are attached form a cyclic structure; and X is anucleophilic substitution leaving group. The conversion of compound (6)to compound (1) is shown in Eq. 2.

[0118] Groups R³, R⁴, and R⁵ independently can vary widely in theirstructures and compositions and remain within the scope of the presentinvention. In one embodiment, R³, R⁴, and R⁵ independently can be H orC₁ to about C₂₀ hydrocarbyl. Preferably, R³, R⁴, and R⁵ independentlycan be H or C₁ to about C₁₀ hydrocarbyl; more preferably independentlyC₁ to about C₁₀ hydrocarbyl; still more preferably independently C₁ toabout C₅ hydrocarbyl. In a preferred embodiment, R³, R⁴, and R⁵independently can be methyl, ethyl, or propyl. For example, R³, R⁴, andR⁵ can each be methyl and the amine of Formula 42 can be trimethylamine.Alternatively, R³, R⁴, and R⁵ can each be ethyl and the amine of Formula42 can be triethylamine.

[0119] In another embodiment, the amine of Formula 42 can comprise aheterocycle as its structure or as one of its substructures. The aminecan have more than one ring and can comprise, for example, a bicyclicheterocycle. In a preferred embodiment, the amine is1,4-diazabicyclo[2.2.2]octane (DABCO) and the benzylammonium compoundhas the structure of Formula 3.

[0120] Groups R¹ and R² can also vary widely in the method of thepresent invention. For example, R¹ and R² independently can be C₁ toabout C₁₀hydrocarbyl; preferably R¹ and R² are independently C₁ to aboutC₅ hydrocarbyl. In one preferred embodiment R¹ and R² are both butyl.

[0121] The benzylammonium compound 1 can be an essentially racemicmixture of enantiomers, or one enantiomer can preponderate over anotherenantiomer. For example, when R¹ and R² are both butyl, compound 1 canbe an essentially racemic mixture of enantiomers or compound 1 cancomprise a (4R,5R) enantiomer that preponderates over a (4S,5S)enantiomer.

[0122] In another preferred embodiment one of R¹ and R² is ethyl and theother of R¹ and R² is butyl. In such a case, compound 1 can be anessentially racemic mixture of enantiomers or compound 1 can comprise a(3R) enantiomer that preponderates over a (3S) enantiomer.Alternatively, compound 1 can comprise a (3S) enantiomer thatpreponderates over a (3R) enantiomer.

[0123] X in the structure of Formula 1 can vary widely and can representessentially any nucleophilic leaving group that produces either apharmaceutically acceptable anion or an anion that can be exchanged fora pharmaceutically acceptable anion. In other words, X⁻ is apharmaceutically acceptable anion or an anion that can be exchanged fora pharmaceutically acceptable anion. For example, X can be chloro,bromo, iodo, methanesulfonato, toluenesulfonato, andtrifluoromethanesulfonato. Preferably X is chloro, bromo, or iodo andmore preferably X is chloro.

[0124] Pharmaceutically acceptable salts are particularly useful asproducts of the methods of the present invention because of theirgreater aqueous solubility relative to a corresponding parent or neutralcompound. Such salts must have a pharmaceutically acceptable anion orcation. Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobrornic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic(including carbonate and hydrogen carbonate anions), sulfonic, andsulfuric acids, and organic acids such as acetic, benzenesulfonic,benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isothionic, lactic, lactobionic, maleic, malic, methanesulfonic,trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, andtrifluoroacetic acids. The chloride salt is particularly preferred formedical purposes. Suitable pharmaceutically acceptable base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, and alkaline earth salts such as magnesium and calcium salts.

[0125] When compound I is formed, it can be used as it is prepared or itcan be further processed. For example, anion X⁻ can be exchanged, forexample by an ion exchange method such as ion exchange chromatography,for any pharmaceutically acceptable anion.

[0126] The amination conditions under which compound 2 and compound 42react to form benzylammonium compound 1 are robust and can vary widely.For example, the amination can be performed neat without a solvent, orthe amination conditions can comprise a solvent. When a solvent isemployed, that solvent can have hydrophilic or hydrophobic properties orit can have both hydrophilic and hydrophobic properties. When thesolvent comprises a hydrophilic solvent, the hydrophilic solvent cancomprise, for example, water; a nitrile such as acetonitrile; an ethersuch as tetrahydrofuran, diethyl ether, or methyl t-butyl ether; analcohol such as methanol, ethanol, isopropyl alcohol, or butanol; aketone such as acetone or methyl ethyl ketone; or an ester such as ethylacetate. When the solvent comprises a hydrophobic solvent, thehydrophobic solvent can comprise, for example, an aliphatic hydrocarbonsolvent such as a C₁ to about C₂₀ aliphatic hydrocarbon; an aromaticsolvent such as benzene, toluene, xylene, or mesitylene; or ahalogenated solvent such as methylene chloride, chloroform, carbontetrachloride, trifluoromethylbenzene, or chlorobenzene. Alternatively,the solvent can comprise a blend of hydrophilic and hydrophobicsolvents. In one preferred embodiment the solvent comprises a blend ofmethyl ethyl ketone and water. In a further preferred embodiment thesolvent comprises a blend of methyl ethyl ketone, toluene, and water.Essentially any solvent that is less nucleophilic than compound 42 canbe used as a solvent in the amination reaction. Preferably the aminationis performed under conditions in which the reagents and product aresubstantially in homogeneous solution during the majority of thereaction.

[0127] The amination can proceed over a wide range of temperatures andpreferably is performed within the range of about 0° C. to about 120°C., more preferably about 15° C. to about 110° C., still more preferablyabout 30° C. to about 100° C., and more preferably still about 45° C. toabout 90° C. The amination conveniently can be performed in refluxingsolvent such as refluxing methyl ethyl ketone. Preferably, the refluxingin methyl ethyl ketone is performed at ambient pressure.

[0128] The derivatization conditions under which benzyl alcohol ethercompound 6 is reacted to form a derivatized benzyl ether compound ofFormula 2 can comprise essentially any conditions known in the art forconverting a benzyl alcohol group into a group that is labile undernucleophilic substitution conditions such as anination conditions. Forexample, the derivatization conditions can comprise contacting compound6 with a halogenating agent. Useful halogenating agents include athionyl halide, a sulfuryl halide, a phosphorus trihalide, a phosphoruspentahalide, an oxalyl halide, and a hydrogen halide. A halogenatingagent useful in the present process is preferably a chlorinating agentor a brominating agent, and more preferably a chlorinating agent. Forexample, the halogenating agent can be thionyl chloride, phosphorustrichloride, phosphorus pentachloride, or hydrogen chloride; preferablythe halogenating agent is selected among thionyl chloride, phosphorustrichloride, and phosphorus pentachloride. More preferably thehalogenating agent is thionyl chloride. Alternatively, the halogenatingagent can comprise a mixture of a phosphine such as triphenylphosphineand a carbon tetrahalide such as carbon tetrachloride. The halogenatingagent can be added to the reaction mixture in any form. For example thehalogenating agent can be added as a solid or as a liquid (for exampleas a liquid above the melting point of the halogenating agent or as asolution in a solvent) or the halogenating agent can be contacted withthe reaction mixture as a gas under ambient, subambient, or elevatedpressure.

[0129] When the halogenating agent is thionyl chloride, the halogenationreaction can be performed under a wide variety of conditions. Thereaction can be run neat or it can be run in the presence of a solvent.A particularly useful solvent is an aprotic solvent. For example, thesolvent can comprise an aromatic solvent, a chlorinated solvent, anether, an amide, an ester, or a hydrocarbon. Preferred solvents includemethylene chloride, chloroform, carbon tetrachloride, chlorobenzene,trifluoromethylbenzene, tetrahydrofuran, diethyl ether, ethyl acetate,and N,N-dimethylacetamide. When the halogenating agent is thionylchloride, the reaction can be performed at essentially any convenienttemperature. Preferably the reaction can run at a temperature of about0° C. to about 150° C., more preferably about 10° C. to about 125° C.,more preferably still about 15° C. to about 100° C., still morepreferably about 20° C. to about 75° C., and more preferably yet about20° C. to about 50° C.

[0130] Alternatively, the derivatization conditions under which compound6 is reacted to form compound 2 can comprise sulfonating the hydroxygroup of compound 6 with a sulfonation reagent to form a sulfonatedcompound, and then treating the sulfonated compound with a source ofhalide such as a hydrogen halide or a halide salt to form compound 2.

[0131] In another embodiment, the derivatization conditions can compriseconditions under which the benzyl hydroxyl group is converted into anoxygen leaving group, for example methanesulfonato, toluenesulfonato,benzenesulfonato, or trifluoromethanesulfonato. Benzyl alcohol ethercompound 6 can for example be treated with a sulfonation reagent such asan alkyl sulfonyl halide reagent or an aryl sulfonyl halide reagent.Such alkyl or aryl sulfonyl halide reagents can include amethanesulfonyl halide, a toluenesulfonyl halide, a benzenesulfonylhalide, or a trifluoromethanesulfonyl halide. Preferably the reagent isan alkyl sulfonyl chloride reagent, an aryl sulfonyl chloride reagent,an alkyl sulfonyl bromide reagent, or an aryl sulfonyl bromide reagent.More preferably the sulfonyl halide reagent is a sulfonyl chloridereagent such as methanesulfonyl chloride, toluenesulfonyl chloride,benzenesulfonyl chloride, or trifluoromethanesulfonyl chloride.

[0132] In the process of the present invention, the benzyl alcohol ethercompound 6 can be used as an essentially racemic mixture of enantiomersor one enantiomer can preponderate over another enantiomer. For example,compound 6 can have a predominantly (4R,5R) absolute configuration or itcan have a predominantly (4S,5S) absolute configuration. Alternatively,compound 6 can comprise a blend of (4R,5R) and (4S,5S) absoluteconfigurations.

[0133] The preparative method of the present invention can furthercomprise a step wherein a phenol compound having the structure ofFormula 4 is contacted with a substituted xylene compound having thestructure of Formula 5 under substitution conditions to produce a benzylalcohol ether compound having the structure of Formula 6 wherein X² is aleaving group. Phenol compound 4 can comprise an essentially racemicmixture or it can comprise predominantly an absolute configuration of(4R,5R). Alternatively, compound 4 can comprise predominantly anabsolute configuration of (4S,5S). The conversion of compound 4 intocompound 6 is shown in Eq. 3.

[0134] X² can be essentially any leaving group known in the art fornucleophilic substitution at benzylic carbon. For example, X² can behalo or a sulfonato group such as methanesulfonato, toluenesulfonato,benzenesulfonato, or trifluoromethanesulfonato. Preferably X² is haloand more preferably it is chloro, bromo, or iodo. More preferably stillX² is chloro.

[0135] The conversion of compound 4 into compound 6 can be performed, ifdesired, in the presence of a solvent. Essentially any solvent thatdissolves to some extent the reactants and that is primarilynon-reactive toward the reactants will be useful. For example, thesolvent can comprise an aromatic solvent, an amide, an ester, a ketone,an ether or a sulfoxide. Preferably, the solvent is an aprotic solventsuch as N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, or anamide solvent. Preferably the solvent is an amide solvent. Morepreferably the amide is selected from the group consisting ofdimethylformamide and dimethylacetamide; and still more preferably thesolvent is N,N-dimethylacetamide (DMAC).

[0136] The conversion of compound 4 into compound 6 can further beperformed in the presence of a base. Useful bases include a metalhydroxide, a metal alcoholate, a metal hydride, an alkyl metal complex,a metal carbonate, and an amide base. Preferably the base comprises ametal hydroxide such as sodium hydroxide, potassium hydroxide, lithiumhydroxide, or calcium hydroxide. More preferably the base is sodiumhydroxide. When the base is a metal carbonate, preferably it is analkali metal carbonate or an alkaline earth metal carbonate. For examplethe base can be potassium carbonate.

[0137] The preparative method of the present invention can furthercomprise a deprotecting step wherein a protected phenol compound havingthe structure of Formula 7

[0138] is deprotected to form the phenol compound 4, wherein R⁶ is aprotecting group. The conversion of compound 7 into compound 4 is shownin Eq. 4. A protecting group is any chemical group that temporarilyblocks a reactive site in a molecule while a chemical reaction isselectively performed at another reactive site in the same molecule orat a reactive site in another molecule residing in the same reactionmixture as the protected molecule. Many protecting groups described byGreene and Wuts (Protective Groups in Organic Synthesis, 3d ed., JohnWiley & Sons, Inc., New York, 1999, pp. 249-287, herein incorporated byreference) are useful for protecting the phenol functional group in theprocess of the present invention. For example, R⁶ can be a hydrocarbylgroup such as a methyl group, an isopropyl group, a t-butyl group, acyclohexyl group, or a benzyl group; an alkoxymethyl group such as amethoxymethyl group or a benzyloxymethyl group; an alkylthiomethyl groupsuch as a methylthiomethyl group; a silyl group such as a trimethylsilylgroup; an acyl group such as a formyl group, an acetyl group, or abenzoyl group; a carbonate group such as a methyl carbonate group; aphosphinate group; or a sulfonate group. In one embodiment, R⁶ is a C₁to about C₁₀ hydrocarbyl group, preferably a C₁ to about C₁₀ alkylgroup, more preferably a C₁ to about C₅ alkyl group, and still morepreferably methyl.

[0139] When R⁶ is a methyl group, a wide variety of conditions can beused in the deprotecting step. For example the conditions of thedeprotecting step can comprise treating compound 7 with a deprotectingreagent. Without limitation, useful deprotecting reagents include ahalotrimethylsilane such as iodotrimethylsilane; an alkali metal such aslithium or sodium in combination with 18-crown-6; an alkali metalsulfide such as sodium sulfide or lithium sulfide; an alkali metalhalide such as lithium iodide; an aluminum trihalide such as aluminumtribromide; an aluminum trihalide and an alkylthiol such as ethanethiol;a strong acid in combination with a source of nucleophilic sulfur; aboron trihalide such as boron tribromide or boron trichloride; ahydrogen halide such as hydrogen iodide, hydrogen bromide, or hydrogeniodide; or a metal hydrocarbyl thiolate. When the deprotecting reagentcomprises a boron trihaiide, preferably it comprises boron tribromide.When the deprotecting reagent is a metal hydrocarbyl thiolate,preferably it is a lithium hydrocarbyl thiolate, more preferably alithium C₁ to about C₁₀ alkyl thiolate, and more preferably stilllithium ethanethiolate. When the deprotecting reagent is a strong acidin combination with a source of nucleophilic sulfur, preferably thestrong acid can for example be sulfuric acid, a sulfonic acid, a Lewisacid, or a phosphorus oxy acid. Preferably the strong acid is sulfuricacid or a sulfonic acid, and more preferably a sulfonic acid. When thestrong acid is a sulfonic acid, preferably it is methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, or toluenesulfonicacid; more preferably the strong acid is methanesulfonic acid. Thesource of nucleophilic sulfur can, for example, be methionine.

[0140] In the method of the present invention, compound 7 can be aracemic compound or it can be used as a mixture of stereoisomers or itcan be used as predominantly one of its stereoisomers. Preferablycompound 7 has an absolute configuration of (4R,5R). Alternatively,compound 7 can have an absolute configuration of (4S,5S).

[0141] When the deprotecting reagent is a sulfonic acid in combinationwith methionine, a variety of conditions can be employed in thedeprotecting step of the present method. The reaction can be runsubstantially neat (substantially without added solvent), or a solventcan be added. Essentially any solvent that dissolves the reagents andthat is mostly unreactive toward the reagents would be useful in thisreaction. Useful solvents include a hydrocarbon solvent such as analkane, an aromatic solvent such as benzene or toluene; a chlorinatedsolvent such as methylene chloride, chloroform, carbon tetrachloride,chlorobenzene, or trifluoromethylbenzene; and inorganic solvents such asSO₂.

[0142] The deprotecting step can be performed over a wide range oftemperatures. Preferably the temperature is in the range of about 0° C.to about 150° C., more preferably about 25° C. to about 130° C., stillmore preferably about 50° C. to about 110° C., and more preferably stillabout 65° C. to about 100° C.

[0143] In another embodiment, the method of the present invention canfurther comprise a cyclization step wherein an amino sulfur oxidealdehyde compound having the structure of Formula 8a is treated undercyclization conditions to form a protected phenol compound having thestructure of Formula 7a wherein R¹, R², and R⁶ are defined above, and yis 1 or 2. The cyclization of 8a into 7a is shown in Eq. 5.

[0144] The cyclization can be mediated by conditions that comprisetreating the amino sulfur oxide aldehyde with a base. Useful bases inthis reaction include MOR¹¹, a metal hydroxide, or an alkyl metalcomplex, wherein R¹¹ is a C₁ to about C₁₀ hydrocarbyl group and M is analkali metal. Preferably the base is MOR¹¹. When the base is MOR¹¹, M ispreferably lithium or potassium. In a particularly useful embodiment R¹¹is a C₁ to about C₁₀ alkyl group, preferably a C₁ to about C₅ alkylgroup, more preferably R¹¹ is methyl, ethyl, isopropyl, or tert-butyl,and still more preferably R¹¹ is tert-butyl.

[0145] The conditions of the cyclization step can comprise a solvent.The solvent can be a hydrophilic solvent and preferably it is ahydrophilic aprotic solvent. The solvent can be, for example, a cyclicor acyclic ether such as tetrahydrofuran, diethyl ether, methyltert-butyl ether, 1,4-dioxane, glyme, or diglyme. Preferably the solventis tetrahydrofuran. Alternatively, the solvent can be an alcohol such asmethanol, ethanol, propanol, isopropyl alcohol, butanol, sec-butylalcohol, isobutyl alcohol, or t-butyl alcohol.

[0146] The cyclization step can be performed at various temperatures.Preferably the step is performed at a temperature of about −20° C. toabout 50° C., preferably about −10° C. to about 35° C., and morepreferably about 0° C. to about 25° C.

[0147] When y is 1, the present method can further comprise an oxidationstep to convert the amino sulfoxide aldehyde (8a where y=1) to the aminosulfone aldehyde (8a where y=2). For example, the oxidation step cancomprise treating the amino sulfoxide aldehyde with sodium hypochlorite.Alternatively, the amino sulfoxide aldehyde can be treated with hydrogenperoxide, preferably in the presence of imidazole andtetraphenylporphyrin Fe(III) chloride. In another alternative, the aminosulfoxide aldehyde can be treated with hydrogen peroxide in the presenceof methyltrioxorhenium. The conversion of the amino sulfoxide aldehydeto the sulfone will also be achieved by treating the sulfoxide withhydrogen peroxide in the presence of acetonitrile and a base such aspotassium carbonate. Another useful oxidation will comprise treating theamino sulfoxide aldehyde with cobalt diacetonylacetonate (Co(acac)₂) inthe presence of O₂ and, for example, isovaleraldehyde. Still anotheruseful oxidation will comprise treating the amino sulfoxide aldehydewith 2-methylpropanal in the presence of O₂. Alternatively, theoxidation will be performed by treating the amino sulfoxide aldehydewith silica gel in the presence of t-butyl hydroperoxide. The conversionwill also occur when the amino sulfoxide aldehyde is treated withperiodic acid in the presence, for example, of ruthenium trichloridehydrate. Alternate conditions for the oxidation can comprise treatingthe amino sulfoxide aldehyde with urea and phthalic anhydride in thepresence of hydrogen peroxide. In another example the oxidation of theamino sulfoxide aldehyde will be carried out by treatment with Oxonemonopersulfate compound (2 KHSO₅. KHSO₄. K₂SO₄) in the presence ofsilica gel or wet montmorillonite clay.

[0148] Preferably y is 2 during the cyclization step.

[0149] In still another embodiment, the method of the present inventioncan further comprise an reductive alkylation step in which a nitrosulfur oxide aldehyde compound having the structure of Formula 9a isreductively alkylated to form the amino sulfur oxide aldehyde compound8b wherein R¹, R², and R⁶ are defined above, and z is 0, 1, or 2.Preferably z is 2. The conditions under which compound 9a is reductivelyalkylated can include, for example, contacting 9a with a source offormaldehyde and a source of H₂ in the presence of a catalyst. Thereductive alkylation is preferably performed at elevated H₂ pressure. Itis useful to perform the reductive alkylation at H₂ pressures rangingfrom about 100 to about 700,000 kPa, preferably from about 200 to about300,000 kPa, more preferably from about 300 to about 100,000 kPa, stillmore preferably from about 350 to about 10,000 kPa, and more preferablystill from about 400 to about 1000 kPa. The conversion of compound 9ainto compound 8b is shown in Eq. 6.

[0150] The reductive alkylation described herein can, if preferred, beperformed on an acetal derivative of compound 9a as shown in Eq. 8b.

[0151] The source of formaldehyde can be essentially any source thatproduces the equivalent of CH₂O. For example, the source of formaldehydecan be formalin, dimethoxymethane, paraformaldehyde, trioxane, or anypolymer of CH₂O. Conveniently the source of formaldehyde can beformalin, and preferably about 30% to about 37% formalin.

[0152] The catalyst for the reductive alkylation can be either aheterogeneous catalyst or a homogeneous catalyst. Preferably thecatalyst is a metal, for example be a noble metal catalyst. Useful noblemetal catalysts include Pt, Pd, Ru, and Rh. Preferably the noble metalcatalyst is a Pd catalyst. Alternatively, the metal catalyst can be anickel catalyst, for example a high-surface area nickel catalyst such asRaney nickel. The catalyst can be a homogeneous catalyst or it can be aheterogeneous catalyst, preferably a heterogeneous catalyst. When thecatalyst is a noble metal catalyst, it can be used either as the metalper se or the metal can be used in combination with a solid support suchas carbon. Alternatively, the metal catalyst can be used in combinationwith another metal such as an anchor metal or a promoter metal. In aparticularly preferred embodiment, the catalyst comprises Pd on carbon.

[0153] An acid can be present in the reaction mixture during thereductive alkylation. Preferably the acid is a strong acid and morepreferably a strong mineral acid. For example, the acid can be sulfuricacid.

[0154] The reaction mixture can conveniently comprise a solvent duringthe reductive alkylation. Useful solvents include an alcohol, anaromatic solvent, an ether solvent, and a halogenated solvent such as ahalogenated aromatic solvent. Preferably the solvent is an alcoholsolvent such as ethanol.

[0155] The reductive alkylation reaction can be run at any convenienttemperature, for example from about 0° C. to about 200° C., preferablyfrom about 10C to about 150° C., more preferably from about 15° C. toabout 125° C., still more preferably from about 20° C. to about 100° C.,more preferably still from about 25° C. to about 80° C., and morepreferably yet from about 30° C. to about 75° C.

[0156] The reductive alkylation can alternatively be performed in twosteps. For example, in a first step the nitro group of compound 9a canbe reduced to an amino group and then the amino group can be methylated.For example, nitro sulfur oxide aldehyde compound 9a can be reduced toform an aniline sulfur oxide compound having the structure of Formula 39

[0157] wherein R¹, R², R⁶ and z are as defined above. The method canfurther comprise a methylation step in which the aniline sulfur oxidecompound is treated under methylation conditions to form the aminosulfur oxide aldehyde compound 8a. The reduction of the nitro group toan amino group can be achieved, for example, by catalytic hydrogenation.The catalytic hydrogenation to form compound 39 will be achieved, forexample by contacting compound 9a with H₂ in the presence of ahydrogenation catalyst. A useful hydrogenation catalyst will be, forexample, a palladium catalyst such as palladium on carbon (Pd/C). Itwill be useful to perform the hydrogenation at H₂ pressures ranging fromabout 100 to about 700,000 kPa, preferably from about 200 to about300,000 kPa, more preferably from about 300 to about 100,000 kPa, stillmore preferably from about 350 to about 10,000 kPa, and more preferablystill from about 400 to about 1000 kPa. The methylation step can becarried out under a wide variety of methylation conditions.Alternatively, the reduction of 9a to form 39 can be performed underother reduction conditions such as treatment of 9a with iron in thepresence of acetic acid or treatment of 9a with tin in the presence ofhydrochloric acid.

[0158] The methylation conditions can comprise, for example, treatingcompound 39 with a methylating reagent such as a methyl halide or amethyl sulfonate. Useful methyl halides include methyl chloride, methylbromide, and methyl iodide. Useful methyl sulfonates include methylmethanesulfonate, methyl toluenesulfonate, methyl benzenesulfonate, andmethyl trifluoromethylsulfonate. Alternatively, the methylationconditions can comprise treating compound 39 with a source offormaldehyde in the presence of H₂ and a hydrogenation catalyst.Conditions useful for the reductive alkylation of compound 9a tocompound 8b are also useful for the methylation of compound 39.

[0159] In another embodiment, the method of the present invention canfurther comprise an oxidation step in which a nitro sulfide aldehydecompound having the structure of Formula 10 is oxidized to form compound9a wherein R⁶ is a protecting group and z is 1 or 2. Preferably,compound 10 is treated under oxidation conditions to form a nitrosulfone aldehyde compound of Formula 9. The oxidation reaction can becarried out by treating 10 with an oxidizing agent. Useful oxidizingagents include, for example, a peracid, an alkyl hydroperoxide, orhydrogen peroxide. When the oxidizing agent is a peracid, it canconveniently be, for example, peracetic acid or m-chloroperbenzoic acid.Preferably the oxidizing agent comprises peracetic acid. The conversionof compound 10 to compound 9a is shown in Eq. 7.

[0160] The method of the present invention can also further comprise astep in which compound 9a where z is 1 is oxidized to sulfone compound9. Such an oxidation can be performed by treating 9a where z is 1 withfor example, a peracid, an alkyl hydroperoxide, or hydrogen peroxide.

[0161] During the oxidation step of Eq. 8 it is convenient to protectthe aldehyde functional group of compound 10 from oxidation, for exampleto prevent the formation of the corresponding carboxylic acid. A varietyof protecting groups are known in the art for protecting aldehydes frombeing oxidized to carboxylic acids and such protecting groups can beemployed in the method of the present invention. Numerous methods ofprotecting aldehydes are described by Greene and Wuts (Protective Groupsin Organic Synthesis, 3d ed., John Wiley & Sons, Inc., New York, 1999,pp. 297-368, herein incorporated by reference) are useful herein. Forexample, the aldehyde group of compound 10 can be protected as an acetalsuch as a dimethyl acetal or a diethyl acetal. Essentially any of theacetal-forming methods described by Greene and Wuts are useful in thepresent invention. It is convenient to protect the aldehyde group of 10as a dimethyl acetal by contacting 10 with trimethyl orthoformate, anacid such as p-toluenesulfonic acid, and methanol. Conveniently, 10 canbe contacted with trimethyl orthoformate, the acid, and methanol in thepresence of a solvent. A useful solvent is benzotrifluoride (BTF). Afterthe oxidation step, the aldehyde group can be deprotected by methodsknown in the art. For example, the dimethyl acetal can be converted tothe aldehyde by treatment with water and an acid such as sulfuric acidor hydrochloric acid.

[0162] Alternatively, the method of the present invention can comprisean oxidation step in which the conditions comprise enantioselectiveoxidation conditions. Such enantioselective oxidation conditions aredescribed in PCT Patent Application No. WO 99/32478, herein incorporatedby reference. For example, nitro sulfide aldehyde compound 10 can beenantioselectively oxidized to a chiral nitro sulfoxide aldehydecompound (9a where z is 1). Ring closure of the chiral nitro sulfoxidealdehyde compound by treatment with base (for example a metal alkoxidesuch as potassium t-butoxide) will form selectively one enantiomer orset of diastereomers of the tetrahydrobenzothiepine-1-oxide compoundthat can be further oxidized selectively to predominantly one enantiomeror selectively to a set of diastereomers of thetetrahydrobenzothiepine-1,1-dioxide.

[0163] The method of the present invention can further comprise asulfide-forming step in which a substituted diphenyl methane compoundhaving the structure of Formula 11 is coupled with a substitutedpropionaldehyde equivalent compound having the structure of Formula 12ain the presence of a source of sulfur to form the nitro sulfide aldehydecompound 10 wherein R¹, R², and R⁶ are defined above; R²⁷ is an aldehydegroup (—CHO) or a protected aldehyde group such as an acetal; X³ is anaromatic substitution leaving group; and X⁴ is a nucleophilicsubstitution leaving group. This overall sulfide-forming step is shownin Eq. 8.

[0164] Where R²⁷ is an aldehyde group, compound 12a has the structure ofFormula 12.

[0165] In the reaction of Eq. 8, it is also possible for R²⁷ to be—CH₂OH (or a protected alcohol) or —CO₂H (or a protected carboxylicacid). Where R²⁷ is —CH₂OH (or a protected alcohol), the addition ofcompound 12a can conveniently be followed by an oxidation step in whichthe alcohol function is oxidized to an aldehyde or carboxylic acidfunction. Where R²⁷ is —CO₂H (or a protected carboxylic acid), theaddition of compound 12a can conveniently be followed by a reductionstep. Alternatively, where R²⁷ is —CO₂H (or a protected carboxylicacid), the addition of compound 12a can be followed by a cyclizationstep and/or a sulfur oxidation step to form a cyclic ketone that can bereduced to alcohol 7a.

[0166] The source of sulfur can be, for example, a metal sulfide such aslithium sulfide (Li₂S), sodium sulfide (Na₂S), or Na₂S₂. Preferably thesource of sulfur is Na₂S or Li₂S, and more preferably Na₂S. X³ can beessentially any convenient aromatic substitution leaving group. Forexample, X³ can be a halogen, a sulfonato group, or a nitro group.Preferably X³ is a halogen, more preferably Cl or Br, and still morepreferably Cl. When X³ is a sulfonato group, it can be, for example,methanesulfonato, trifluoromethanesulfonato, benzenesulfonato, ortoluenesulfonato; preferably X³ is trifluoromethane-sulfonato. When X³is a sulfonato group, the sulfide-forming reaction is preferably carriedout in the presence of a noble metal such as Pd(0) and a metal sulfide.

[0167] X⁴ can be essentially any nucleophilic substitution leaving groupthat, when displaced, produces an anion that is chemically andphysically compatible with the reaction conditions. For example, X⁴ canbe chloro, bromo, iodo, methanesulfonato, toluenesulfonato, andtrifluoromethanesulfonato. Preferably X⁴ is chloro, bromo, or iodo andmore preferably X⁴ is bromo.

[0168] In the sulfide-forming step of the present reaction, it ispreferred that diphenylmethane compound 11 be contacted with the sourceof sulfur to form the intermediate thiolate anion 44 before beingcontacted with the substituted propionaldehyde compound 12.

[0169] In the sulfide-forming step of the present inventive method, thecontacting of the source of sulfur with compound 11 can be done at anyconvenient temperature. Preferably the contacting is performed at atemperature in the range of about 0° C. to about 150° C., morepreferably about 0° C. to about 100° C., still more preferably about 10°C. to about 75° C., still more preferably about 20° C. to about 50° C.,and more preferably yet around 25° C. to about 45° C. It is helpful toallow the source of sulfur, for example sodium sulfide, to contactcompound 11 for a period of reaction time before adding substitutedpropionaldehyde compound 12 to the mixture. Appropriately, the reactiontime can be about 5 minutes to about ten hours, preferably about 10minutes to about 7 hours, more preferably about 20 minutes to about 5hours, and more preferably still about 30 minutes to about 3 hours.

[0170] Optionally, anion 44 can be quenched, for example with water orwith an acid, to form thiol compound 45. Thiol 45 can be isolated,stored, transported, or kept in a solution until used. When ready to usethiol 45 to prepare compound 10, thiol 45 can be treated with a suitablebase such as a metal alkoxide, a metal hydride, an alkyl metal complex,or other base to form anion 44. Suitable bases include, for example, analkali metal alkoxide such as sodium methoxide, lithium methoxide,sodium ethoxide, lithium ethoxide, and potassium t-butoxide. Usefulmetal hydrides include sodium hydride and calcium hydride.

[0171] However, it is preferred not to quench anion 44 or to isolatethiol compound 45. Anion 44 is sufficiently stable to store or transportwithout quenching. Alternatively, the addition of the source of sulfurand the reaction with the substituted propionaldehyde compound 12 can beperformed in one reaction vessel or in one reaction mixture withoutisolation of intermediate structures.

[0172] Alternatively, the sulfide-forming step can be performedfollowing the reaction of Eq. 8a, wherein diphenylmethane compound 11 iscontacted under coupling conditions described above with a thiopropylcompound 12b to form sulfide 10a. In Eq. 8a, R¹, R², R⁶, R²⁷, and X³ areas defined above and R²⁸ is H or a labile thiol protecting group such asan acyl group, preferably an acetyl group.

[0173] The reaction of Eq. 8a can conveniently be performed in thepresence of a base. Useful bases include an alkali metal base or analkaline earth metal base. Useful alkali metal bases include alkalimetal hydroxides such as sodium hydroxide or potassium hydroxide.Conveniently, the reaction of Eq. 8a can be performed in the presence ofa solvent, preferably an aprotic solvent, and more preferably a polaraprotic solvent. A preferred solvent for the reaction of Eq. 8a is DMSO.

[0174] Conveniently, the sulfide-forming step of Eq. 8a can be performedin the presence of a solvent. Useful solvents include polar aproticsolvents. Without limitation, useful polar aprotic solvents includeN,N-dimethylacetamide (DMAC), dimethylsulfoxide (DMSO),dimethylformamide (DMF), and N-methylpyrrolidone (NMP). Preferably thesolvent is DMAC.

[0175] Where R²⁷ of Eq. 8a is a protected aldehyde group such as anacetal group, compound 10a can be further reacted to deprotect theprotected acetal group, if desired. Alternatively, compound 10a can bedirectly oxidized under sulfide oxidizing conditions described herein toform sulfone compound 10c. If desired, compound 10c can be treated underreductive alkylation conditions described herein to form a dimethylaminoaldehyde compound 10b as shown in Eq. 8b.

[0176]FIG. 1 shows an overall process by which substitutedpropionaldehyde compound 12 can be prepared. Compound 12 can be made,for example, by reacting a diol compound having the structure of Formula37 in the presence of a carbonyl compound having the structure ofFormula 38 and a source of X⁴ to form an acid ester having the structureof Formula 36. X⁶ can be hydroxy, halo, or —OC(O)R¹⁸; preferably hydroxyor halo. When X⁶ is halo, preferably it is chloro, bromo, or iodo; morepreferably chloro. Alternatively X⁶ can be hydroxy. When X⁶ is hydroxy,the reaction of compound 37 with the carbonyl compound 38 isadvantageously performed in the presence of a strong acid, preferably astrong mineral acid. Useful strong acids include HCl, HBr, HI, sulfuricacid, or a sulfonic acid. Useful sulfonic acids include methanesulfonicacid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, andbenzenesulfonic acid. Preferably the strong acid is HBr. R¹⁰ and R¹⁸independently can be C₁ to about C₂₀ hydrocarbyl; preferably C₁ to aboutC₁₀ alkyl; more preferably C₁ to about C₅ alkyl; more preferably stillmethyl, ethyl, or isopropyl; and still more preferably methyl. R¹, R²,and X⁴, are as defined above. The source of X⁴ can be, for example, asource of halide. The source of halide can be any source in which thehalide can nucleophilically displace an acyloxy group such as —OC(O)R¹⁰.For example, the source of halide can advantageously be the strong acidwhen the strong acid is HCl, HBr, or HI. Preferably the source of halideis a source of bromide such as NaBr, LiBr, or HBr. When the source ofbromide is NaBr or LiBr, it is advantageous to perform the reaction inthe presence of an acid catalyst. Preferably the source of halide is HBror HI, more preferably HBr. Advantageously, the reaction to formcompound 36 can be performed over a wide range of temperatures.Preferably the reaction is performed from about 50° C. to about 175° C.,more preferably about 65° C. to about 150° C., still more preferablyabout 70° C. to about 130° C.

[0177] Acid ester 36 can be solvolyzed to form a substituted propanolcompound having the structure of Formula 35. The solvolysis reaction canbe performed under conditions known in the art for the solvolysis ofcarboxylic acid esters without displacing X⁴. It is convenient toperform the solvolysis in the presence of an acid catalyst. A usefulacid catalyst can be a mineral acid or an organic acid. When the acidcatalyst is a mineral acid, it can be for example a hydrogen halideacid, sulfuric acid, or a sulfonic acid. Useful sulfonic acids includemethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, andtrifluoromethanesulfonic acid. Useful hydrogen halide acids includehydrochloric acid, hydrobronic acid, and hydroiodic acid; preferablyhydrobromic acid. The solvolysis can be performed in the presence of asolvent. Preferably the solvent is a C₁ to about C₁₀ alcohol solvent;more preferably a C₁ to about C₅ alcohol solvent; still more preferablymethanol, ethanol, propanol, or 2-propanol; and more preferably stillethanol.

[0178] The reactions to form compounds 36 and 35 can be performedseparately with individual isolation of the products. Alternatively, thereactions can be performed in a single reaction vessel or in a singlereaction medium without isolation of compound 36.

[0179] The substituted propanol compound 35 can be oxidized to form thesubstituted propionaldehyde compound 12. This can be achieved bycontacting compound 35 with an oxidizing agent. Oxidation conditionsshould be appropriate to those in which an alcohol group is oxidized inthe presence of X⁴. For example, the oxidizing conditions can comprise amild oxidizing agent such as sulfur trioxide-pyridine complex. Otheruseful oxidizing conditions include, for example, contacting 35 withoxalyl chloride and triethylamine in the presence of a reactant such asDMSO. Another example of useful oxidizing conditions comprise contacting35 with sodium hypochlorite in the presence of2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO). When theoxidizing agent is sulfur trioxide-pyridine complex, the oxidation canadvantageously be performed at a temperature from about 10° C. to about100° C.; preferably about 20° C. to about 75° C.; more preferably about20° C. to about 50° C. The oxidation can be performed in the presence ofa solvent. Useful solvents include for example a sulfoxide such as DMSO;or a chlorinated solvent such as methylene chloride, chloroform, orcarbon tetrachloride. When the oxidizing agent is sulfurtrioxide-pyridine complex, the complex can be added to the reactionmixture either as a slurry in a solvent or, preferably, as a solid addedover a period of time (for example about 1 to about 15 hours).

[0180] In one preferred embodiment of the preparation of compound 12,both R¹ and R² are butyl. In an alternative preferred embodiment, one ofR¹ and R² is ethyl and the other of R¹ and R² is butyl. When one of R¹and R² is ethyl and the other of R¹ and R² is butyl, compound 12 canhave an R absolute configuration about the quaternary carbon atom.Alternatively, compound 12 can have an S absolute configuration aboutthe quaternary carbon atom.

[0181] The reactions described herein that are useful for thepreparation of compound 12 can be performed individually or incombination. FIG. 2 shows a preferred process by which2,2-dibutyl-3-bromopropionaldehyde can be prepared using the methods ofthe present invention.

[0182] One embodiment of the present invention is shown in Eq. 8cwherein compound 12b can have the structure of compound 12d. Eq. 8c isexemplary of a large variety of methods by which thioacyl acetalcompounds useful in the present invention can be made in which the acylgroup and the acetal group can independently vary widely in structure.In Eq. 8c bromoaldehyde compound 53 is treated with potassiumthioacetate to form thioacetyl aldehyde compound 12c. Compound 12c istreated with a trialkyl formate such as triethylformate in the presenceof an acid catalyst such as a sulfonic acid catalyst (preferablytoluenesulfonic acid) to form compound 12d, wherein Et is ethyl. Theacetal-forming step can be performed, if desired, in the presence of asolvent, for example an alcohol solvent. When the acetal formed is anethyl acetal, the solvent can conveniently be ethanol.

[0183]FIG. 1 a shows a representative overall process by which nitrosulfide acetal compound 67 (10a wherein R¹ and R² are both butyl and R²⁷is a diethylacetal group) can be prepared and by which compound 67 canbe used to produce compound 29.

[0184] Compound 12b can, if desired, be prepared by a number of othermethods. For example, acrolein compound 77 can be contacted withthioacyl compound 78 to form acylthiomethyl aldehyde compound 79 asshown in Eq. 8d. In Eq. 8d, R²⁹ can be C₁ to about C₂₀ hydrocarbyl,preferably C₁ to about C₁₀ hydrocarbyl, more preferably C₁ to about C₅hydrocarbyl, and still more preferably ethyl or butyl. R³⁰ can be C₁ toabout C₂₀ hydrocarbyl, preferably C₁ to about C₁₀hydrocarbyl, morepreferably C₁ to about C₅ hydrocarbyl, and still more preferably methyl.Preferably the reaction of Eq. 8d is performed in the presence of a basecatalyst such as an amine catalyst. For example the amine catalyst canbe an alkylamine such as trialkylamine.

[0185] Compound 79 can be contacted with compound 20 to formacylthiomethyl alkene aldehyde compound 80 as shown in Eq. 8e. Thereaction in Eq. 8e is preferably performed in the presence of an acidcatalyst, preferably a sulfur acid catalyst such as sulfuric acid or asulfonic acid. For example the acid catalyst can be p-toluenesulfonicacid, benzenesulfonic acid, methanesulfonic acid, ortrifluoromethanesulfonic acid. The reaction can conveniently be carriedout under heating conditions, for example at a temperature of about 50°C. to about 150° C., preferably about 75° C. to about 125° C., morepreferably about 100° C. to about 115° C.

[0186] Compound 80 can be derivatized under acetal-forming conditions toform unsaturated acetal compound 81. In compound 81, R³¹ and R³²independently can be C₁ to about C₂₀ alkoxy or, together with the carbonatom to which they are attached can form a cyclic acetal. Where R³¹ andR³² are alkoxy, preferably they are C₁ to about C₁₀ alkoxy, morepreferably C₁ to about C₅ alkoxy, more preferably still methyl or ethyl,and still more preferably ethyl. Where R³¹ and R³² together form acyclic acetal, preferably they form an ethylene glycol acetal or a1,3-propanediol acetal, more preferably an ethylene glycol acetal. Forexample, compound 80 can be contacted with an alcohol or a mixture ofalcohols in the presence of a catalyst such as an acid catalyst.Alternatively, compound 80 can be treated with an orthoformate such astriethyl orthoformate or trimethyl orthoformate to form the acetal.

[0187] Compound 81 can be reduced to produce thiomethyl acetal compound82. It will be apparent to one of skill in the art given the presentdisclosure that compound 82 can be used in place of compound 12b in thereaction of Eq. 8a to form sulfide 10a. Reduction conditions to convertcompound 81 to compound 82 can vary widely. For example, compound 81 canbe treated with a hydrazide such as p-toluenesulfonyl hydrazide in thepresence of an amine such as piperidine to form compound 82.

[0188] Once the nitro sulfide aldehyde compound 10 is formed in thesulfide-forming step, 10 can be isolated by methods known in the art orit can be oxidized to form nitro sulfone aldehyde compound 9 by methodsdescribed above. While intermediate compounds can optionally beisolated, stored, or transported, it is convenient to perform thesulfide-forming step and the oxidation step in one reaction vesselwithout isolation of intermediate structures.

[0189] The method of the present invention can further comprise areduction step in which a substituted benzophenone compound 13

[0190] is reduced to form the substituted diphenyl methane compound 11wherein R⁶ and X³ are defined above. The reduction step is shown in Eq.9. For example, the reduction step can be carried out by contactingcompound 13 with trifluoromethanesulfonic acid (triflic acid) and asilane such as triethyl silane. It is useful to perform the reductionstep in the presence of a solvent, for example a strong acid solventsuch as trifluoroacetic acid. When trifluoroacetic acid is used as asolvent, the triflic acid is preferably used in a catalytic amount.Particularly, it is useful to dissolve 13 in trifluoroacetic acid, addthe triflic acid, and then add triethyl silane. Reaction temperatureduring the addition of the triethyl silane can be controlled, ifnecessary, by cooling. The reaction temperature can be controlled in therange of about 25° C. to about 100° C., preferably about 30° C. to about75° C., and more preferably about 45° C. to about 50° C. Other silanesare useful in the present reaction also, for example, polymethylhydrosiloxane (PMHS) or other trialkylsilanes.

[0191] Alternatively, the reduction of 13 to 11 can be carried out in asolvent such as methylene chloride in the presence of triflic acid and asilane such as triethyl silane. When trifluoroacetic acid is absent fromthe reaction mixture, typically a larger-than-catalytic amount oftriflic acid is required. Another method of reducing 13 to 11 willcomprise treating 13 with a Lewis acid such as aluminum chloride and asilane such as triethyl silane. In another alternative, the reductioncan be carried out by treating 13 with sodium borohydride in thepresence of a catalyst. In a further alternative, the reduction can becarried out by treating 13 with sulfuric acid in the presence of a noblemetal catalyst such as a palladium catalyst, preferably Pd/C. In a stillfurther alternative, 13 can be reduced to the corresponding alcohol, forexample with a borohydride such as sodium borohydride. The resultingalcohol can be treated, for example, with sodium borohydride and asilane such as triethylsilane. The alcohol can be reduced to 11 by othermeans, for example treating the alcohol with a sulfonating reagent suchas methanesulfonyl chloride or toluenesulfonyl chloride and thentreating the resulting sulfonic acid ester with sodium borohydride.

[0192] The method of the present invention can also further comprise anacylation step in which a protected phenol compound having the structureof Formula 14

[0193] is treated with a substituted benzoyl compound having thestructure of Formula 15

[0194] under acylation conditions to produce a substituted benzophenonecompound having the structure of Formula 13 wherein R⁶ and X³ aredefined above; X⁵ can be hydroxy, halo, or —OR¹⁴; and R¹⁴ can be an acylgroup. This overall acylation step is shown in Eq. 10.

[0195] The acylation conditions can comprise Friedel-Crafts acylationconditions. For example the acylation conditions can further comprise aLewis acid. Useful Lewis acids include aluminum-containing Lewis acidssuch as an aluminum trihalide; boron-containing Lewis acids such asboron trifluoride, boron trifluoride etherate, or boron trichloride;tin-containing Lewis acids such as SnCl₄; halogen-containing Lewis acidssuch as HF; iron-containing Lewis acids such as FeCl₃;antimony-containing Lewis acids such as SbF₅; and zinc-containing Lewisacids such as ZnI₂ or ZnCl₂. When the Lewis acid is an aluminumtrihalide, preferably it is AlCl₃ or AlBr₃, more preferably AlCl₃.Alternatively, the Lewis acid can be supported on a solid support suchas a clay. For example, the Lewis acid can comprise an FeCl₃ on claycomposition such as Envirocat.

[0196] Alternatively, the acylation can be run in the presence of astrong protic acid such as sulfuric acid; a phosphoric acid, for exampleo-phosphoric acid or polyphosphoric acid (PPA); or a sulfonic acid, forexample p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonicacid, or trifluoromethanesulfonic acid.

[0197] X⁵ can be hydroxy, halo, or —OR¹⁴. For example, X⁵ can behydroxy, bromo, iodo, or —OR¹⁴.

[0198] When X⁵ is halo, preferably it is chloro, bromo, or iodo. In oneuseful embodiment X⁵ is chloro. In another useful embodiment X⁵ is bromoor iodo, preferably bromo. When X⁵ is halo, it is preferred that theacylation conditions further comprise a Lewis acid as described above,for example an aluminum trihalide. Useful aluminum trihalides includealuminum tribromide and aluminum trichloride, preferably aluminumtrichloride.

[0199] When X⁵ is hydroxy, it is preferred that the acylation conditionsfurther comprise a strong protic acid. Some useful strong protic acidsinclude sulfuric acid, a sulfonic acid, or a phosphorus oxy acid. Usefulphosphorus oxy acids include orthophosphoric acid (commonly known asphosphoric acid, H₃PO₄), pyrophosphoric acid (H₄P₂O₇), or polyphosphoricacid (PPA). Preferably the phosphorus oxy acid is phosphoric acid orpolyphosphoric acid, preferably polyphosphoric acid. Combinations ofphosphorus oxy acids are also useful in the present invention. Thephosphorus oxy acid can be added as the acid per se or it can begenerated in situ, for example by the hydrolysis of a phosphorus halidecompound such as PCl₅ or by the hydrolysis of a phosphorus oxidecompound such as P₂O₅.

[0200] When R¹⁴ is —OR¹⁴ and R¹⁴ is an acyl group, compound 15 is acarboxylic acid anhydride. The acid anhydride can have a symmetricalstructure; i.e., X⁵ can have the structure of Formula 46. Alternatively,the acid anhydride can be a mixed anhydride. For example R¹⁴ can be aformyl group, an acetyl group, a benzoyl group or any other convenientacyl group.

[0201] When X⁵ is —OR¹⁴, it is preferred that the acylation conditionsfurther comprise a Lewis acid as described above, for example analuminum trihalide. Useful aluminum trihalides include aluminumtribromide and aluminum trichloride, preferably aluminum trichloride.

[0202] An alternative method for the preparation of compound 13 is shownin Eq. 11. When X⁵ of compound 15 is halo or —OR¹⁴, compound 15 can betreated with compound aryl metal complex 56 wherein L is ametal-containing moiety and R⁶ is as defined above. The group L can be,for example, MgX⁶, Na, or Li, wherein X⁶ is a halogen. When L is MgX⁶(in other words, when 56 is a Grignard reagent), X is preferably Br, Cl,or I; more preferably Br or Cl.

[0203] The present inventive method can further comprise one or moresteps wherein a nitro alkenyl aldehyde compound having the structure ofFormula 16 is reduced and reductively alkylated to form an amino alkylaldehyde compound having the structure of Formula 17 (Eq. 12) wherein R¹and R⁶ are defined above, R⁷ is H or C₁ to about C₁₇ hydrocarbyl, and tis 0, 1, or 2. Preferably R⁷ is a C₁ to about C₁₀alkyl group, morepreferably a C₁ to about C₅ alkyl group, still more preferably C₁ toabout C₃ alkyl group, and more preferably still methyl. Preferably t is2.

[0204] The reduction and reductive alkylation of compound 16 to compound17 can be performed in a single step or it can be performed in discretesteps. For example, the reduction of the double bond can be done at thesame time as the reductive alkylation of the nitro group. Alternatively,the aliphatic C—C double bond in compound 16 can be reduced to a singlebond in a step that is discrete from the reductive alkylation of thenitro group to the dimethylamino group. As another alternative, in afirst step the nitro group and the alkene double bond of compound 16 canbe reduced to an amino group and to an alkyl group, respectively, andthen the amino group can be methylated. The reduction of the nitro groupand the alkene double bond will be readily performed with the use of ahydrogenation catalyst as is known in the art. Such a reduction will runin the presence of H₂. The methylation of the reduced amino group can beperformed with essentially any methylating agent as is known in the art,for example a methyl halide such as methyl iodide, methyl bromide, ormethyl chloride. Another useful methylating agent is dimethyl sulfate.

[0205] The conditions under which compound 16 is reduced and reductivelyalkylated can include, for example, contacting 16 with a source offormaldehyde and a source of H₂ in the presence of a catalyst. Theconversion is preferably performed at elevated H₂ pressure. It is usefulto perform the conversion at H₂ pressures ranging from about 100 toabout 700,000 kPa, preferably from about 200 to about 300,000 kPa, morepreferably from about 300 to about 100,000 kPa, still more preferablyfrom about 350 to about 10,000 kPa, and more preferably still from about400 to about 1000 kPa.

[0206] The source of formaldehyde can be essentially any source thatproduces the equivalent of CH₂O. For example, the source of formaldehydecan be formalin, an acetal of formaldehyde such as dimethoxymethane,paraformaldehyde, trioxane, or any polymer of CH₂O. Conveniently thesource of formaldehyde can be formalin, and preferably about 35% toabout 37% formalin.

[0207] The catalyst for the reduction and reductive alkylation can beeither a heterogeneous catalyst or a homogeneous catalyst. Preferablythe catalyst is a metal, for example the catalyst can be a noble metalcatalyst. Useful noble metal catalysts include Pt, Pd, Ru, and Rh.Preferably the noble metal catalyst is a Pd catalyst. The noble metalcatalyst can be used either in a homogeneous or in a heterogeneous form.When used in a heterogeneous form, the catalyst can be used, forexample, as the metal per se or on a solid support such as carbon or analuminum oxide. In a particularly preferred embodiment, the catalystcomprises palladium and more preferably Pd on carbon. In anotherembodiment the catalyst comprises a nickel catalyst such as ahigh-surface area nickel catalyst. A useful high-surface area nickelcatalyst is Raney nickel.

[0208] An acid can be present in the reaction mixture during thereduction and reductive alkylation. Preferably the acid is a strong acidand more preferably a strong mineral acid. For example, the acid can besulfuric acid.

[0209] A solvent can conveniently be present in the reaction mixtureduring the reduction and reductive alkylation. Useful solvents includean alcohol, an ether, a carboxylic acid, an aromatic solvent, an alkane,a cycloalkane, or water. Preferably the solvent is an alcohol solventsuch as a C₁ to about C₁₀alcohol; more preferably a C₁ to about C₅alcohol; and more preferably still methanol, ethanol, propanol, orisopropyl alcohol. In a particularly preferred embodiment, the solventis ethanol.

[0210] The reduction and reductive alkylation reaction can be run at anyconvenient temperature, for example from about 0° C. to about 200° C.,preferably from about 10° C. to about 150° C., more preferably fromabout 15° C. to about 100° C., still more preferably from about 20° C.to about 75° C., more preferably still from about 25° C. to about 60°C., and more preferably yet from about 30° C. to about 40° C.

[0211] Alternatively, the conversion of 16 into 17 can be performed indiscrete steps. For example, in a first step the nitro group and thealkene double bond of compound 16 can be reduced to an amino group andto an alkyl group, respectively. In a second step the amino group can bemethylated. The reduction of the nitro group and the alkene double bondcan be readily performed with the use of a hydrogenation catalyst as isknown in the art. Such a reduction will run in the presence of H₂. Themethylation of the reduced amino group can be performed with essentiallyany methylating agent as is known in the art, for example a methylhalide such as methyl iodide, methyl bromide, or methyl chloride.Another useful methylating agent is dimethyl sulfate.

[0212] An alternative route to compound 17 is shown in Eq. 13, wherein uof compound 16a is 0 or 1 (in other words, when compound 16a is asulfide or a sulfoxide compound). In the instant route, compound 16a canbe reduced by methods described herein (for example by contacting 16awith H₂ and a hydrogenation catalyst such as Pd/C) to form compound 57wherein u is 0 or 1, R¹, R⁶, and R⁷ are as defined above, and R¹⁹ can be—NH₂, —NHOH, or —NO₂. Compound 57 can be oxidized (for example bymethods described herein for the conversion of sulfides or sulfoxides tosulfones) to compound 58 wherein R¹, R⁶, and R⁷ are as defined above,and R²⁰ can be —NH₂, —NHOH, or —NO₂. Compound 58 can be alkylated orreductively alkylated by methods described herein to form compound 17wherein t is 2.

[0213] The method of the present invention can further comprise athermolysis step wherein an acetal compound having the structure ofFormula 18

[0214] is thermolyzed to form the nitro alkenyl aldehyde compound 16,wherein R¹, R⁶, and t are defined above; R⁷ can be H or C₁ to about C₁₇hydrocarbyl; and R¹³ can be H or C₁ to about C₂₀ hydrocarbyl. Thethermolysis step is shown in Eq. 14. Preferably t is 2. Preferably R⁷ isa C₁ to about C₁₀ alkyl group, more preferably a C₁ to about C₅ alkylgroup, still more preferably C₁ to about C₃ alkyl group, and morepreferably still methyl. R¹³ is preferably a C₁ to about C₁₀hydrocarbylgroup, more preferably a C₁ to about C₁₀ alkenyl group, still morepreferably a C₁ to about C₅ alkenyl group, and more preferably still aC₁ to about C₄ alkenyl group. In one preferred embodiment, R¹³ is agroup having the structure of Formula 43 wherein R⁷ is as defined above.Preferably R¹³ is 1-buten-3-yl.

[0215] The thermolysis reaction can advantageously be performed in thepresence of a base. Useful bases include without limitation a metalhydride, a metal hydroxide, a metal carbonate, or a metal bicarbonate.Preferably the base is a metal hydride such as calcium hydride, lithiumhydride, sodium hydride, or potassium hydride. More preferably the baseis calcium hydride. Other useful bases include sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, potassiumbicarbonate, or sodium bicarbonate. The thermolysis reaction can be run,for example, by contacting compound 18 with the base over a period oftime, preferably under essentially anhydrous conditions. Surprisingly,the presence of a soluble base such as triethylamine or pyridine duringthe conversion of 18a to 47 can be advantageously used to slow thereaction rate relative to reaction conditions in which the soluble baseis absent. The thermolysis can be run in the presence of a solvent.Essentially any solvent that is unreactive under the thermolysisreaction conditions is useful. Aprotic solvents are especially usefuland aromatic solvents are preferred, such as benzene, toluene, o-xylene,m-xylene, p-xylene, mesitylene, and naphthalene. Especially preferredsolvents include toluene, o-xylene, m-xylene, p-xylene, or mesitylene;more preferably toluene, o-xylene, m-xylene, or p-xylene; and morepreferably still toluene or o-xylene. Other useful solvents include anether such as tetrahydrofuran, diethyl ether, or diphenyl ether; anester such as ethyl acetate; an alcohol such as ethanol or t-butylalcohol; or a ketone such as acetone or benzophenone.

[0216] In another embodiment, the thermolysis can be performed neat,i.e., in the absence of a solvent. For example, compound 18 can beheated neat to produce compound 16a. When compound 18 is heated neat,the thermolysis can be run, if desired, at subambient pressure. Forexample, the thermolysis can be run at a pressure at which eliminationproducts produced by the thermolysis boil away. Operating the reactionunder such conditions will aid in driving the thermolysis reaction tocompletion. Advantageously, the reaction pressure during the thermolysiscan be less than about 760 mmHg (101 kPa), preferably less than about500 mmHg (66.6 kPa), more preferably less than about 250 mmHg (33.3kPa), more preferably still less than about 100 mmHg (13.3 kPa), stillmore preferably less than about 50 mmHg (6.7 kPa), and more preferablyyet less than about 10 mmHg (1.3 kPa).

[0217] The thermolysis can be run over a wide range of temperatures. Forexample the thermolysis can be run at a temperature in the range ofabout 10° C. to about 250° C., preferably about 50° C. to about 200° C.,more preferably about 75° C. to about 175° C. and more preferably stillabout 100° C. to about 150° C. Conveniently the thermolysis can be runin a refluxing solvent, for example refluxing o-xylene. Alternatively,the thermolysis can be performed at pressures above ambient pressure,thereby allowing the reaction to proceed at temperatures above theambient-pressure boiling point of the solvent.

[0218] The thermolysis reaction is preferably performed under dry oressentially anhydrous conditions and in the absence of acid to preventreverse reaction and byproduct formation.

[0219] Without intending to limit the scope of the present invention,the thermolysis reaction to form compound 16 is believed to proceed bythe intermediacy of an enol ether compound. For example, bis-butenylacetal compound 18a is thought to eliminate a molecule of 3-buten-2-olto form enol ether 47 (a pre-Claisen intermediate) as shown in Eq. 15.Compound 47 is then believed to undergo a [3,3]-sigmatropic shift (alsoknown as a Claisen rearrangement) to form butenyl sulfone aldehydecompound 31 as shown in Eq. 16. Although compound 47 is shown herein ashaving a E-configuration across the double bond between themethanesulfonyl moiety and the alkoxy moiety, it is also possible thatthis compound can form in the Z-configuration.

[0220] The conversion of 18a to 31 can be carried out for example byheating at 145° C. a toluene or o-xylene solution of a mixturecomprising 18a or a mixture of 18a and 47, preferably in the presence ofcalcium hydride. Alternatively, the conversion of 18a to 31 can beachieved by filtering crude 18a through an acidic medium such as silicagel or a basic medium such as basic alumna prior to heating.

[0221] The addition of soluble bases such as triethylamine or pyridineduring the conversion of 18a to 47 can be used, if desired, to decreasethe thermolysis reaction rate relative to the situation in which thesoluble base is absent.

[0222] Compound 18 can be prepared by a step in which a monoalkylaldehyde compound having the structure of Formula 19 is reacted with anallyl alcohol compound having the structure of Formula 20 in thepresence of a hydroxylated solvent having the structure HOR¹³ to form anacetal compound having the structure of Formula 18, wherein R¹, R⁶, R⁷,R¹³, and t are as defined above. Preferably t is 2. In a preferredembodiment, R¹³ has the structure of Formula 43. For example, thisembodiment can be realized if the allyl alcohol compound 20 itself isused as a hydroxylated solvent, preponderating over another hydroxylatedsolvent or essentially in the absence of another hydroxylated solvent.The conversion of compound 19 into compound 18 is shown in Eq. 17.

[0223] Acetal compound 18 can be prepared by numerous methods employingvarious conditions known in the art. The reaction to form the acetal ispreferably performed in the presence of an acid catalyst. The catalystcan be, for example, a strong acid such as sulfuric acid, hydrochloricacid, phosphorous acid, phosphoric acid, trifluoroacetic acid, or asulfonic acid. Useful sulfonic acids include methanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonicacid. However, organic acids and acidic heterogeneous catalysts alsowork to mediate this reaction, for example pyridiniump-toluenesulfonate, acetic acid, propionic acid, Amberlyst 15, acidiczeolites, acidic clay, Pd(PhCN)₂Cl₂, and AlCl(CH₂CH₃)₂. Virtually anyBronsted-Lowry or Lewis acid can be employed as a catalyst. Theacetal-forming reaction can if desired be performed in the presence of asolvent. Useful solvents include chlorinated solvents such as methylenechloride, chloroform, or carbon tetrachloride; aromatic solvents such asbenzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, ortrifluoromethylbenzene; aprotic solvents including CH₃CN, ethyl acetate,isopropyl acetate, butyl acetate, tetrahydrofuran, methyl isobutylketone, 1,4-dioxane; or alcohols such as 3-buten-2-ol. The reaction canbe run at essentially any convenient temperature that does not lead tosignificant degradation of starting material or product. For example,the temperature can be in the range of about 0° C. to about 200° C.;preferably about 20° C. to about 150° C.; more preferably about 30° C.to about 135° C. The reaction can be performed in a refluxing solventsuch as refluxing methylene chloride. The conversion can conveniently beperformed during azeotropic removal (distillation) of the solvent andwater. For example, the conversion can be achieved during azeotropicremoval of toluene (about 105° C. to about 115° C.) or of xylene (about125° C. to about 135° C.).

[0224] Optionally, removal of water during the reaction or concomitantwith the reaction can advantageously be used to increase conversion oryield. Without meaning to limit the scope of the invention, it isbelieved that removal of water drives the acetal-forming reaction towardcompletion. For example, process apparatus similar to a Dean-Stark trapor azeotropic distillation equipment can be used to remove water. Othermethods such as molecular sieve (zeolites), isopropenyl acetate, andtrimethyl orthoformate can also be used.

[0225] Advantageously, the conversion of 18a to 47 and the conversion of47 to 31 can be carried out sequentially or simultaneously in a singlereaction vessel or in a single reaction mixture without isolation. Tofurther advantage, the preparation of the acetal 18 from aldehyde 19,the conversion of 18 to the corresponding enol ether intermediate, andthe conversion of the enol ether intermediate to 31 can all be carriedout in a single reaction vessel or reaction mixture. For example,2-(((4-methylphenyl)sulfonyl)methyl)hexanal can be heated in a solventsuch as toluene in the presence of 3-buten-2-ol and p-toluenesulfonicacid with removal of water (e.g., with a Dean-Stark trap) to produce2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hex-4-enal.

[0226] This useful and surprising overall method for preparing a2-alkenyl-2,2disubstituted aldehyde 49 has general applicability. Thegeneral method can be employed in the conversion of a3-sulfur-propionaldehyde compound 48 to the 3-sulfur-propionaldehydeolefin compound 49 as shown in Eq. 18. Conditions described above forthe conversion of compound 19 to compound 16 are useful in the broadreaction of Eq. 18.

[0227] In the reaction of Eq. 18:

[0228] R¹⁵ is selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, alkylaryl, arylalkylaryl, and acyl, wherein alkyl,alkenyl, alkynyl, aryl, alkylaryl, arylalkylaryl, and acyl optionallyare substituted with at least one R²² group;

[0229] R¹⁶, R¹⁷, R^(21a), and R^(21b) are independently selected fromthe group consisting of H and hydrocarbyl;

[0230] R²² is selected from the group consisting of H, —NO₂, amino, C₁to about C₁₀ alkylamino, di(C₁ to about C₁₀)alkylamino, C₁ to aboutC₁₀alkylthio, hydroxy, C₁ to about C₁₀alkoxy, cyanato, isocyanato,halogen, OR⁶, SR⁶, SR⁶R^(6a), and NR⁶R^(6a);

[0231] R⁶ and R^(6a) independently are selected from the groupconsisting of H and a protecting group; and

[0232] q is 0, 1, or 2.

[0233] Preferably R¹⁵ is selected from the group consisting of aryl,alkylaryl, and arylalkylaryl. More preferably R¹⁵ is selected from thegroup consisting of aryl, alkylaryl, and arylalkylaryl, wherein aryl,alkylaryl, and arylalkylaryl are optionally substituted with at leastone R²² group. More preferably still, R¹⁵ is arylalkylaryl optionallysubstituted with at least one R²² group, and more preferably still R¹⁵is 2-(phenylmethyl)phenyl optionally substituted with at least one R²²group. R¹⁵ therefore can include without limitation any of the moietiesshown in Table A, wherein R⁶ is as defined above. TABLE A NumberStructure 59a

59b

59c

59d

59e

59f

59g

59h

59i

59j

[0234] When R¹⁶ is hydrocarbyl, it can be unsubstituted hydrocarbyl, forexample C₁ to about C₁₀ alkyl and preferably C₁ to about C₅ alkyl. Morepreferably, when R¹⁶ is unsubstituted hydrocarbyl, it is ethyl or butyl.

[0235] In the reaction of Eq. 18, R¹⁷ is preferably hydrocarbyl, morepreferably C₁ to about C₁₀ alkyl, still more preferably C₁ to about C₅alkyl, and more preferably still methyl.

[0236] R^(21a) and R^(21b) preferably independently are selected fromthe group consisting of H, C₁ to about C₁₀ alkyl, C₂ to about C₁₀alkenyl, and C₂ to about C₁₀ alkynyl; more preferably R^(21a) andR^(21b) are both H.

[0237] Preferably q is 2 in the reaction of Eq. 18.

[0238] The reaction of Eq. 18 can be run at essentially any convenienttemperature that does not lead to significant degradation of startingmaterial or product. For example, the temperature can be in the range ofabout 0° C. to about 200° C.; preferably about 20° C. to about 150° C.;more preferably about 30° C. to about 135° C.; and more preferably stillabout 30° C. to about 100° C.

[0239] Compound 48 can be prepared by any of a variety of methods. Forexample, 48 can be prepared by the reaction of Eq. 18a wherein anacrolein compound (5) is treated with a nucleophilic organosulphurcompound (66) to produce compound 48. The reaction of Eq. 18a ispreferably performed in the presence of a base, preferably an amine, andmore preferably an alkylamine such as triethylamine. Preferably the baseis present in a catalytic amount. In Eq. 18a R¹⁵, R¹⁶, R^(21a), R^(21b),and q are as defined above.

[0240] The monoalkyl sulfone aldehyde compound 19 can be prepared in asulfone-forming reaction by treating a substituted diphenyl methanecompound 11 under sulfination conditions and coupling it with a2-substituted acrolein compound having the structure of Formula 21 toform compound 19. The sulfone-forming reaction is shown in Eq. 19.

[0241] The sulfination conditions can comprise, for example, treatingcompound 11 with a source of a metal sulfide such as Na₂S, Na₂S₂, orLi₂S, preferably Na₂S₂. The sulfination conditions can further comprisewater. After treating with the metal sulfide, the substrate can beoxidized to form sulfinic acid 51 or a salt thereof (Eq. 20). A varietyof oxidizing conditions can be used to effect this oxidation. Forexample, a useful oxidizing agent includes a source of hydrogenperoxide.

[0242] During the addition of the metal sulfide, the temperature of themixture can vary over a wide range. It is useful to react compound 11with the metal sulfide at a temperature of about 25° C. to about 125°C., preferably about 40° C. to about 100° C., and more preferably about50° C. to about 80° C. This reaction can be run in the presence of asolvent. Essentially any solvent into which hydrogen peroxide candissolve is useful for the present reaction. Useful solvents include analcohol such as a C₁ to about C₁₀alcohol; preferably a C₁ to about C₅alcohol; more preferably methanol, ethanol, propanol, or 2-propanol;still more preferably ethanol. Other useful solvents include amides suchas dimethylacetamide. During the oxidation with hydrogen peroxide, thereaction is preferably maintained at less than about 30° C., morepreferably less than about 25° C., more preferably less than about 20°C. If desired, sulfinic acid compound 51 can be isolated as the acid or,preferably, as a salt.

[0243] Alternatively, 51 can be further used with or without isolation.For example, 51 can be treated with acrolein compound 21 to producemonoalkyl sulfone aldehyde compound 19. The reaction with compound 21can be done at essentially any convenient temperature, including ambienttemperature. The present reaction can also be run in the presence of asolvent. Useful solvents include nitriles such as acetonitrile; aromaticsolvents such as benzene, toluene, o-xylene, m-xylene, p-xylene, ormesitylene; or chlorinated solvents such as methylene chloride. In oneembodiment, the present reaction is run under biphasic conditions in thepresence of tetrabutylammonium iodide.

[0244] When R⁶ is methyl and when R¹ is 2-butylacrolein, the product ofthe sulfone-forming step is butyl sulfone aldehyde 32.

[0245] The reactions described herein can be run individually, forexample to prepare intermediate compounds for storage, use in otherreactions, or for commerce. Alternatively two or more of the reactionscan be combined. For example, an overall process for the preparation ofbenzylammonium compound 1 is shown in FIG. 3. Methods and reagentsdescribed in this disclosure can be used in the process of FIG. 3.Diphenyl methane compound 11 can, if desired, be prepared by the processshown in FIG. 4, also using methods and reagents described herein.

[0246] The methods described herein can also be combined with otherreactions in the art and still be within the scope and spirit of thepresent invention. For example, PCT Patent Application No. WO 99/32478describes a method of preparing an enantiomerically enrichedtetrahydrobenzothiepine oxide such as compound (4R,5R)-24 (Example 9 inWO 99/32478) using an asymmetric oxidizing agent. The process of FIG. 5shows one of many ways in which an enantiomerically enrichedtetrahydrobenzothiepine oxide 24 (for example (4R,5R)-24) can be used incombination with the methods of the present invention to prepare anenantiomerically enriched benzylammonium compound (for example (4R,5R)-1and more specifically (4R,5R)-41). The enantiomerically enrichedcompound 24 as used can be prepared as in WO 99/32478 or it can beprepared using methods disclosed hereinbelow. As used herein, asterisksin chemical structures represent chiral centers.

[0247] Other methods can alternatively be used in the process of thepresent invention to obtain an enantiomerically enriched benzylammoniumcompound. For example, one of the intermediates or products having oneor more chiral centers in FIG. 3 can be optically resolved. An opticalresolution is any technique by which an enantiomer of a compound isenriched in concentration relative to another enantiomer of thecompound. Useful methods of optical resolution includeco-crystallization with a chiral agent, for example as a salt with anoptically active counterion, i.e., crystallization of a diastereomericsalt. Another useful technique for the optical resolution of thecompounds in the present invention is to derivatize a compound havingone or more chiral centers with an optically active derivatizing agentthereby forming a diastereomeric derivative. The diastereomericderivative can then be separated into its individual diastereomers forexample by fractional crystallization or chromatography.

[0248] Another method useful for optically resolving intermediates orproducts in the present process is chiral chromatography. Any of severaltypes of chiral chromatography can be used in the instant invention. Forexample, the chiral chromatographic technique can include continuouschromatography, semi-continuous chromatography, or single column (batch)chromatography. An example of continuous chromatography is simulatedmoving bed chromatography (SMB). U.S. Pat. No. 2,985,589, hereinincorporated by reference, describes the general theory of SMB. Anotherreference that describes the general theory of SMB is U.S. Pat. No.2,957,927, herein incorporated by reference. Still another referencedescribing SMB is U.S. Pat. No. 5,889,186.

[0249] Still another chiral chromatographic technique useful in thepresent invention is a semi-continuous technique such as closed-looprecycling with periodic intra-profile injection (CLRPIPI). CLRPIPI isdescribed by C. M. Grill in J. Chrom. A, 796, 101-113 (1998).

[0250] Single column or batch chromatography is also useful in thepresent invention for performing the optical resolution.

[0251] In any of the chiral chromatographic techniques referencedherein, a variety of conditions can be used. Each of the techniquesrequires a stationary phase and a mobile phase. The stationary phase cancomprise a chiral substrate. For example the chiral substrate cancomprise a saccharide or a polysaccharide such as an amylosic,cellulosic, xylan, curdlan, dextran, or inulan saccharide orpolysaccharide. The chiral substrate optionally can be on a solidsupport such as silica gel, zirconium, alumina, clay, glass, a resin, ora ceramic. The chiral substrate can, for example, be absorbed by thesolid support, adsorbed onto the solid support, or chemically bound tothe solid support. Alternatively, the stationary phase can compriseanother chiral substrate such as a tartaric acid derivative. In anotheralternative, the stationary phase can comprise a derivatized silicasorbent such as a Pirkle sorbent.

[0252] The chiral chromatographic technique of the present inventionalso comprises a mobile phase. Any mobile phase that is capable ofdifferentially partitioning each enantiomer between the stationary phaseand the mobile phase is useful in the present invention. For example,the mobile phase can comprise water, an alcohol, a hydrocarbon, anitrile, an ester, a chlorinated hydrocarbon, an aromatic solvent, aketone, or an ether. If the mobile phase comprises an alcohol,preferably it is a C₁ to about C₁₀ alcohol, more preferably a C₁ toabout C₈ alcohol, and more preferably a C₁ to about C₅ alcohol. If themobile phase comprises a hydrocarbon, preferably it is a C₁ to about C₂₀hydrocarbon, more preferably a C₁ to about C₁₋₅ hydrocarbon, and stillmore preferably a C₁ to about C₁₀ hydrocarbon. Other useful solventsinclude acetonitrile, propionitrile, ethyl acetate, methylene chloride,toluene, benzene, xylene, mesitylene, acetone, methyl t-butyl ether, ordiethyl ether. Preferably the mobile phase comprises acetonitrile,toluene, or methyl t-butyl ether. The mobile phase can also comprise amixture of solvents. A preferred mobile phase mixture comprises tolueneand methyl t-butyl ether. The mobile phase can also comprise asupercritical fluid such as supercritical CO₂. Carbon dioxide can alsobe used as a mobile phase in a subcritical state such as liquid CO₂.Supercritical or subcritical CO₂ can also be used in combination withany of the other mobile phases mentioned above.

[0253] The chiral separation can be performed at any convenienttemperature, preferably about 5° C. to about 45° C., more preferablyabout 20° C. to about 40° C.

[0254] The optical resolution can be performed on any convenientcompound or intermediate having a chiral center in the preparation ofthe benzylammonium compound. For example, the optical resolution can beperformed on any one or more of compounds 1, 2, 4, 6, 7, 8, 9, 10, 12,35, 36, or 37. In one preferred embodiment, the optical resolution isperformed on compound 7. A further preferred embodiment is one in whichcompound 7 is represented by compound 24, preferably compound syn-24.

[0255] Typically in an optical resolution, two enantiomers are partiallyor essentially completely separated from each other. If the goal of theseparation is to obtain an enriched sample of one desired enantiomer, itis useful to have a method of converting or recycling the otherenantiomer into the desired enantiomer or into an essentially racemicmixture of enantiomers so that further optical resolution can beperformed. Where more than one chiral center exists in a molecule, aplurality of diastereomers can exist. Similarly, diastereomers can beseparated to obtain an enriched sample of one or more desireddiastereomers. It is further useful to have a method of converting oneor more other diastereomers into the desired diastereomer(s) or into amixture of diastereomers so that further separation can be performed.

[0256] Surprisingly, it has been found that this conversion or recycleof stereoisomers can be performed in the process of the presentinvention. As used herein the word “stereoisomer” includes enantiomerand diastereomer. A method is now disclosed of treating a stereoisomerof a tetrahydrobenzothiepine compound 22

[0257] wherein Formula 22 comprises a (4,5)-stereoisomer selected fromthe group consisting of a (4S,5S)-diastereomer, a (4R,5R)-diastereomer,a (4R,5S)-diastereomer and a (4S,5R)-diastereomer, to produce a mixturecomprising the (4S,5S)-diastereomer and the (4R,5R)-diastereomer,wherein the method comprises contacting a base with a feedstockcomposition comprising the (4,5)-stereoisomer of thetetrahydrobenzothiepine compound, thereby producing a mixture ofdiastereomers of the tetrahydrobenzothiepine compound; and wherein:

[0258] R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl;

[0259] R⁸ is selected from the group consisting of H, hydrocarbyl,heterocyclyl, ((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl,((heterocycloalkyl)alkylaryl)alkyl, ((quaternaryheterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl,

[0260] wherein hydrocarbyl, heterocycle, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, and quaternary heteroarylalkyloptionally have one or more carbons replaced by a moiety selected fromthe group consisting of O, NR³, N⁺R³R⁴A⁻, S, SO, SO₂, S⁺R³A⁻, PR³,P⁺R³R⁴A⁻, P(O)R³ phenylene, carbohydrate, amino acid, peptide, andpolypeptide, and

[0261] R⁸ is optionally substituted with one or more moieties selectedfrom the group consisting of sulfoalkyl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴,P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

[0262] R³, R⁴, and R⁵ are as defined above;

[0263] R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M;

[0264] A⁻ is a pharmaceutically acceptable anion and M is apharmaceutically acceptable cation;

[0265] R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

[0266] n is a number from 0 to 4;

[0267] X⁷ is S, NH, or O; and

[0268] x is 1 or 2.

[0269] Preferably the group X⁷R⁸ in compound 22 is in the 3′ or the 4′position of the phenyl group, more preferably the 4′ position.Preferably X⁷ is NH or O, more preferably O.

[0270] A wide variety of bases can be used to effect the conversion orrecycle of stereoisomers of the present invention. For example, the basecan be an alkali metal hydroxide, an alkaline earth metal hydroxide, analkali metal alkoxide, a metal hydride, an alkali metal amide, and analkali metal hydrocarbyl base. Preferably the base is an alkali metalamide, a metal hydride, or an alkali metal alkoxide. Useful alkali metalamides include lithium diethylamide (LDA), lithium diisopropylamide,lithium N-methylanilide, lithium methylamide, potassium amide, sodamide,and ((CH₃)₃Si)₂NNa. Useful metal hydrides include lithium hydride,sodium hydride, and calcium hydride. Useful alkali metal alkoxidesinclude for example a lithium alkoxide, a sodium alkoxide, and apotassium alkoxide; preferably a sodium alkoxide or a potassiumalkoxide. The alkoxide is preferably a C₁ to about C₁₀alkoxide; morepreferably a C₁ to about C₆ alkoxide; still more preferably a C₁ toabout C₅ alkoxide such as a methoxide, an ethoxide, a n-propoxide, anisopropoxide, a n-butoxide, a sec-butoxide, an isobutoxide, at-butoxide, or a t-amylate. A particularly useful alkoxide is potassiumt-butoxide. R⁸ can be for example H, C₁ to about C₂₀ alkyl,hydroxyalkylarylalkyl, or heterocycloalkylalkylarylalkyl. Preferably R⁸is H, or C₁ to about C₂₀ alkyl; more preferably C₁ to about C₂₀ alkyl;still more preferably C₁ to about C₁₀ alkyl; and more preferably stillC₁ to about C₅ alkyl. In a particularly preferred embodiment R⁸ ismethyl. R⁹ can for example be H, amino, alkylamino, alkoxy, or nitro;preferably H or alkylamino, more preferably alkylamino, and morepreferably still dimethylamino. In a particularly preferred embodiment,R⁹ is dimethylamino and n is 1. When R⁹ is dimethylamino and n is 1, itis preferred that R⁹ be located at the 7-position of thetetrahydrobenzothiepine compound structure. R¹ and R² are as definedabove. In one preferred embodiment both of R¹ and R² are butyl. Inanother preferred embodiment one of one of R¹ and R² is ethyl and theother of R¹ and R² is butyl. It is preferred that the (4,5)-stereoisomerof compound 22 is a (4S,5S) diastereomer, a (4R,5S) diastereomer, or a(4S,5R) diastereomer; more preferably a (4S,5S) diastereomer. Thepresent conversion conditions can also comprise a solvent. Usefulsolvents include any solvent that is essentially non-reactive toward thebase under the reaction conditions. Preferred solvents include etherssuch as tetrahydrofuran, diethyl ether, or dioxane; or alcohols such asa C₁ to about C₁₀ alcohol. If the solvent is an alcohol, preferably itis a C₁ to about C₆ alcohol; more preferably methanol, ethanol,propanol, isopropyl alcohol, butanol, t-butyl alcohol, or t-amylalcohol; still more preferably ethanol, t-butyl alcohol, or t-amylalcohol; and more preferably still t-butyl alcohol. The conversion ofthe present invention is particularly advantageous when thetetrahydrobenzothiepine compound has the structure of Formula 24.

[0271] The feedstock composition used in the stereoisomeric conversionof the present invention can further comprise amino sulfone aldehydecompound 8 wherein R¹, R², and R⁶ are as defined above.

[0272] An alternate method for the stereoisomeric conversion of thepresent invention comprises treating compound 22 under eliminationconditions to produce a dihydrobenzothiepine compound having thestructure of Formula 23

[0273] and oxidizing the dihydrobenzothiepine compound to produce themixture of stereoisomers including the (4S,5S)-diastereomer and the(4R,5R)-diastereomer. R¹, R², R⁸, R⁹, n, X⁷, and x are as defined above.The elimination conditions can comprise an acid or the conditions cancomprise a base, or the elimination conditions can occur at a neutralpH. The elimination conditions can further comprise derivatizing thediastereomer of a tetrahydrobenzothiepine compound to form atetrahydrobenzothiepine derivative having an elimination-labile group atthe 4-position, and eliminating the elimination-labile group to form thedihydrobenzothiepine compound. The elimination-labile group can be, forexample, acid labile or base labile. The elimination-labile group canalso be thermally labile. For example, it can be an acetate group or a3-buten-2-oxy group. The oxidation step can comprise an alcohol-formingstep in which the dihydrobenzothiepine compound is reacted underalcohol-forming conditions to produce a mixture of stereoisomers of thetetrahydrobenzothiepine compound. For example the alcohol-formationconditions can comprise oxymercuration-demercuration. In anotherexample, the alcohol-formation conditions can comprise epoxidationfollowed by reduction using conditions described in PCT PatentApplication No. WO 97/33882, herein incorporated by reference.Preferably the (4,5)-stereoisomer is selected from the group consistingof a (4S,5S) diastereomer, a (4R,5S) diastereomer, and a (4S,5R)diastereomer; more preferably a (4S,5S) diastereomer. In a particularlypreferred embodiment, the tetrahydrobenzothiepine compound has thestructure of compound 24 and the dihydrobenzothiepine compound has thestructure of compound 25.

[0274] It would be particularly useful to have a form of thetetrahydrobenzothiepine compounds that is easily handled, reproduciblein form, easily prepared, and that is nonhygroscopic. A hygroscopiccompound can absorb water, for example from the ambient atmosphere, anda sample of the compound can gain weight as more water is absorbed.Absorbance of water into a sample of a compound can also affectmeasurements of the compound, for example, infrared spectra.Hygroscopicity of a pharmaceutical compound can be problematic if thatcompound absorbs water to an extent and at such a rate that weighing andmeasurement of the compound is made difficult. Accurate weighing andmeasurement of a pharmaceutical compound is important to assure thatpatients receive an appropriate dose.

[0275] Crystal forms of the tetrahydrobenzothiepine compounds describedherein and particularly of compound 41 are now disclosed.

[0276] A first crystal form (Form I) of compound 41 or its enantiomerhas a melting point or a decomposition point of about 220° C. to about235° C., preferably about 228° C. to about 232° C., and more preferablyabout 230° C. Form I can be prepared, for example, by crystallization ofcompound 41 or its enantiomer from a solvent that comprisesacetonitrile, methanol, or methyl t-butyl ether. Preferably, Form I canbe prepared by crystallization of compound 41 or its enantiomer from asolvent comprising methanol or methyl t-butyl ether, and more preferablyfrom a solvent comprising methanol and methyl t-butyl ether. Methods forthe preparation of Form I include those described in U.S. Pat. No.5,994,391, herein incorporated by reference, examples 1426 and 1426a.

[0277] Another crystal form (Form II) of compound 41 or its enantiomerhas a melting point or a decomposition point of about 278° C. to about285° C. Form II can be prepared, for example, by crystallization ofcompound 41 or its enantiomer from a solvent, preferably a ketonesolvent, more preferably a ketone solvent comprising methyl ethyl ketone(MEK) or acetone. By way of example, compound 41 or its (4S,5S)enantiomer can be mixed in a solvent comprising MEK and Form II can beinduced to crystallize from that solution. Preferably, compound 41 orits (4S,5S) enantiomer is dissolved in a solvent comprising a ketonesuch as MEK and a quantity of water (for example about 0.5% to about 5%water by weight, preferably 1% to about 4% water by weight, and morepreferably 2% to about 4% water by weight). The crystallization can beinduced, for example, by evaporating the solvent (e.g., by distillationor by exposure to a stream of a gas such as air or nitrogen for a periodof time) or by evaporating the water (e.g. by distillation orazeotroping). Alternatively, the crystallization will be induced byother traditional crystallization methods such as chilling or byaddition of another solvent or by addition of a seed crystal. As anotheralternative, crystallization can be induced by adding additional MEK(decreasing the % by weight of water in the crystallization solvent).Form II can conveniently be caused to precipitate from a reactionmixture in which compound 41 is prepared (e.g., the reaction of(4R,5R)-27 with DABCO) by running that reaction in a solvent comprisingMEK, and preferably in a solvent comprising MEK and about 0.5% to about5% by weight of water. The precipitation can be facilitated bydistilling solvent off of the reaction mixture.

[0278] Therefore in one embodiment, the present invention provides thetetrahydrobenzothiepine compound in a useful crystalline form.Particularly, the present invention provides a crystalline form (i.e.,Form II) of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71 andwherein the crystalline form has a melting point or a decompositionpoint of about 278° C. to about 285° C. Preferably, Form II has amelting point or a decomposition point of about 280° C. to about 283°C., and more preferably about 282° C.

[0279] Preferably, the compound of Formula 71 has an absoluteconfiguration of (4R,5R) (i.e., compound 41) and this is a preferredabsolute configuration for the compound forming the crystal structure ofForm II. However, the (4S,5S) enantiomer of compound 71 can also beprepared in the crystalline form of the present invention.

[0280]FIG. 6 shows typical X-ray powder diffraction patterns for Form I(plot (a)) and Form II (plot (b)) of compound 41. Preferably the Form IIcrystalline form has the X-ray powder diffraction pattern shown in FIG.6, plot (b). Typically, Form II has an X-ray powder diffraction patternwith peaks at about 9.2 degrees 2 theta, about 12.3 degrees 2 theta, andabout 13.9 degrees 2 theta. The Form II X-ray powder diffraction patterntypically lacks peaks at about 7.2 degrees 2 theta and at about 11.2degrees 2 theta. Table 1 shows a comparison of prominent X-ray powderdiffraction peaks for Form I and Form II.

[0281]FIG. 7 shows typical Fourier transform infrared (FTIR) spectra forForm I (plot (a)) and Form II (plot (b)) for compound 41. Preferably theForm II crystalline form has the infrared (1R) spectrum shown in FIG. 7,plot (b). Typically, Form II has an IR spectrum with a peak at about3245 cm⁻¹ to about 3255 cm⁻¹. Preferably, Form II also has an IR peak atabout 1600 cm⁻¹. Also preferably, Form II has an IR peak at about 1288cm⁻¹. Table 2 shows a comparison of prominent FTIR peaks for Form I andForm II.

[0282]FIG. 8 shows typical solid state carbon-13 nuclear magneticresonance (NMR) spectra for Form I (plot (a)) and Form II (plot (b)) ofcompound 41. Preferably the Form II crystalline form has the solid statecarbon-13 NMR spectrum shown in FIG. 8, plot (b). Typically, Form II hasa solid state carbon-13 NMR spectrum with peaks at about 142.3 ppm,about 137.2 ppm, and about 125.4 ppm. Table 3 shows a comparison ofprominent solid state carbon-13 NMR peaks for Form I and Form II.

[0283]FIG. 9 shows typical differential scanning calorimetry profilesfor Form I (plot (a)) and Form II (plot(b)) of compound 41.

[0284] A dry sample of the crystalline form having a melting point or adecomposition point of about 278° C. to about 285° C. (i.e., Form II)typically gains less than about 1% of its own weight when equilibratedunder 80% relative humidity (RH) air at 25° C. Such a crystalline formis essentially nonhygroscopic. For example, when a sample of Form IIcrystalline form of compound 41 or an enantiomer thereof is dried atessentially 0% RH at about 25° C. under a purge of essentially drynitrogen until the sample exhibits essentially no weight change as afunction of time, the sample gains less than 1% of its own weight whenit is then equilibrated under about 80% RH air at about 25° C. For thepresent purposes, the term “essentially 0% RH” means less than about 1%RH. The term “equilibrated” means that the change in weight of a sampleover time at a given relative humidity is less than 0.0003%((dm/dt)/m₀×100, where m is mass in mg, m₀ is initial mass, and t istime in minutes).

[0285] The present invention also provides a crystalline form of atetrahydrobenzothiepine compound wherein the tetrahydrobenzothiepinecompound has the structure of Formula 71 wherein the crystalline form isproduced by crystallizing the tetrahydrobenzothiepine compound from asolvent comprising methyl ethyl ketone. Preferably in the crystallineform of the present invention, compound 71 has a (4R,5R) absoluteconfiguration; i.e., compound 41. Alternatively, a crystal form of thepresent invention can be prepared by crystallizing the(4S,5S)-enantiomer of compound 71 from a solvent comprising methyl ethylketone.

[0286] The present invention provides a method of preparing thecrystalline form of the present invention. Particularly, the presentinvention provides a method for the preparation of a crystalline form ofa tetrahydrobenzothiepine compound having the structure of Formula 63

[0287] wherein the method comprises crystallizing thetetrahydrobenzothiepine compound from a solvent comprising methyl ethylketone, and wherein:

[0288] R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl;

[0289] R³, R⁴, and R⁵ independently are selected from the groupconsisting of H and C₁ to about C₂₀ hydrocarbyl, wherein optionally oneor more carbon atom of the hydrocarbyl is replaced by O, N, or S, andwherein optionally two or more of R³, R⁴, and R⁵ taken together with theatom to which they are attached form a cyclic structure;

[0290] R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, 3 heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

[0291] R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M;

[0292] n is a number from 0 to 4;

[0293] A⁻ and Q⁻ independently are pharmaceutically acceptable anions;and

[0294] M is a pharmaceutically acceptable cation.

[0295] Preferably in the method of the present invention thetetrahydrobenzothiepine compound has the structure of Formula 64, andmore preferably it has the structure of compound 41.

[0296] The present invention also provides a crystal form of compound 41or an enantiomer thereof wherein the crystalline form is produced bycrystallizing the tetrahydrobenzothiepine compound or the enantiomerfrom a solvent comprising a ketone solvent. Preferably the ketonesolvent is methyl ethyl ketone, acetone, or methyl isobutyl ketone. Morepreferably the ketone is methyl ethyl ketone.

[0297] Another aspect of the present invention embodies a method for thepreparation of Form II (“product crystal form”) of compound 41 from FormI (“initial crystal form”) of compound 41 wherein the method comprisesapplying heat to Form I. Accordingly, the present invention provides amethod for the preparation of a Form II of a tetrahydrobenzothiepinecompound having the compound structure of Formula 41 wherein Form II hasa melting point or a decomposition point of about 278° C. to about 285°C., wherein the method comprises applying heat to Form I of thetetrahydrobenzothiepine compound wherein Form I has a melting point or adecomposition point of about 220° C. to about 235° C., thereby formingForm II of compound 41. Conveniently in the present method Form I isheated to a temperature from about 20° C. to about 150° C., preferablyabout 50° C. to about 125° C., and more preferably about 60° C. to about1001C. The method can further comprise a cooling step after the step inwhich Form I is heated. If desired, the conversion of Form I into FormII can be performed in the presence of a solvent. For example, theconversion can be performed on a slurry of Form I mixed with a solvent.The solvent can comprise essentially any convenient solvent. Preferablythe solvent comprises a ketone, and more preferably the ketone is methylethyl ketone, acetone, or methyl isobutyl ketone. More preferably stillthe ketone is methyl ethyl ketone. However, the conversion can ifdesired be performed in acetone. Alternatively, the conversion can beperformed in methyl isobutyl ketone.

[0298] Although the discussion and examples of this applicationillustrate the preparation of tetrahydrobenzothiepine oxides having apara-substituted phenyl group at the 5-position of the benzothiepinering, tetrahydrobenzothiepine oxides having a meta-substituted phenylgroup at the 5-position can be prepared in a similar manner by selectionof the proper starting materials. For example, use of a meta-substitutedphenyl analog of a compound of Formula 7 in the applicable processes ofthe present application would yield the correspondingtetrahydrobenzothiepine oxide having a meta-substituted phenyl group atthe 5position. The preparation of selected suitable starting materialsis disclosed in U.S. Pat. No. 5,994,391 (such as described in Examples1398a, 1400, 1425, 1426 and 1426a).

[0299] c. Detailed Preparative Methods

[0300] The starting materials for use in the methods of preparation ofthe invention are known or can be prepared by conventional methods knownto a skilled person or in an analogous manner to processes described inthe art.

[0301] Generally, the process methods of the present invention can beperformed as follows.

EXAMPLE 1 Preparation of1-chloro-2-(4-methoxyphenyl)methyl-4-nitrobenzene, 33

[0302]

[0303] Step A. Preparation of 2-chloro-5-nitrophenyl-4′-methoxyphenylketone, 34.

[0304] Method 1.

[0305] In an inert atmosphere, weigh out 68.3 g of phosphoruspentachloride (0.328 mole, Aldrich) into a 2-necked 500 mL round bottomflask. Fit the flask with a N₂ inlet adapter and suba seal. Remove fromthe inert atmosphere and begin N₂ purge. Add 50 mL of anhydrouschlorobenzene (Aldrich) to the PCl₅ via syringe and begin stirring witha magnetic stir bar.

[0306] Weigh out 60 g of 2-chloro-5-nitrobenzoic acid (0.298 mole,Aldrich). Slowly add the 2-chloro-5-nitrobenzoic acid to thechlorobenzene solution while under N₂ purge. Stir at room temperatureovernight. After stirring at room temperature for about 20 hrs, place inan oil bath and heat at 50° C. for 1 hr. Remove chlorobenzene under highvacuum. Wash the residue with anhydrous hexane. Dry the acid chloride(wt=61.95 g). Store in inert and dry atmosphere.

[0307] In an inert atmosphere, dissolve the acid chloride in 105 mL ofanhydrous anisole (0.97 mole, Aldrich). Place solution in a 2-neck 500mL round bottom flask.

[0308] Weigh out 45.1 g of aluminum trichloride (0.34 moles, Aldrich)and place in a solid addition funnel. Fit the reaction flask with anaddition funnel and a N₂ inlet adapter. Remove from inert atmosphere.Chill the reaction solution with an ice bath an begin the N₂ purge.Slowly add the AlCl₃ to the chilled solution. After addition iscomplete, allow to warn to room temperature. Stir overnight.

[0309] Quench the reaction by pouring into a solution of 300 mL 1N HCland ice. Stir for 15 min. Extract twice with ether. Combine the organiclayers and extract twice with 2% NaOH, then twice with deionized H₂O.Dry over MgSO₄, filter, and rotovap to dryness. Remove the anisole underhigh vacuum. Crystallize the product from 90% ethanol/10% ethyl acetate.Dry on a vacuum line. Wt=35.2 g. yield 41%. Mass spec (m/z=292).

[0310] Method 2.

[0311] Change 230 kg of 2-chloro-5-nitrobenzoic acid (CNBA) to a cleandry reactor flushed with N₂. Seal the reactor and flush with N₂. To thereactor charge 460 kg of anisole. Start agitation and heat the mixtureto 90° C., dissolving most of the CNBA. To the reactor charge 785 kg ofpolyphosphoric acid (PPA). PPA containers are warmed in a hot box (70°C.) prior to charging in order to lower viscosity. Two phases result.The upper phase contains the majority of the CNBA and anisole. The lowerphase contains most of the PPA. The reaction conditions are maintainedfor 5 hr at which time sampling begins to determine residual CNBA.Analysis of samples is by gas chromatography. The reaction is quenchedwhen 1.0% residual CNBA is achieved. The reaction is quenched into 796kg H₂O. The temperature of the quenched mass is adjusted to 60° C. andmaintained at this temperature until isolation. Agitation is stopped andthe phases are split. The lower spent acid phase is sent to wastedisposal. The upper product phase is washed with 18 kg of sodiumbicarbonate in 203 kg of water, then washed with 114 kg of potablewater. Agitation is stopped and the phases are split. The upper aqueousphase is sent to waste disposal. The lower product phase is cooled toabout 0° C. and 312 kg of heptane is added. A mixture of ortho- andpara-substituted product (total 10 kg) precipitates out of solution andis recovered by pressure filtration. To the product phase is addedanother 134 kg of heptane causing another 317 kg of a mixture of ortho-and para-substituted product to precipitate. The precipitate isrecovered by pressure filtration. The wetcake is washed with heptane toremove residual anisole. The wetcake is dried in a rotary vacuum dryerat 60° C. Final yield of 34 is 65.1% (30.3% yield of theortho-substituted product).

[0312] Step B. Preparation of1-chloro-2-(4-methoxyphenyl)methyl-4-nitrobenzene, 33.

[0313] To a clean dry nitrogen purged 500 mL round bottom flask wascharged 60.0 g (0.206 moles) of 34. Trifluoroacetic acid (100 grams, ca.67 mL) was added to the reactor and the resulting suspension was heatedto 30° C. to give a homogeneous wine colored solution. Next, 71.0 g(0.611 moles) of triethylsilane was placed in an addition funnel and 1.7g (0.011 moles) of trifluoromethanesulfonic acid (triflic acid) wasadded to reactor. The color changed from burgundy to greenish brown.Triethylsilane was added dropwise to the solution at 30° C. The batchcolor changed to a grass green and an exothermic reaction ensued. Theexotherm was allowed to raise the batch temperature to 45° C. withminimal cooling in a water bath. The reaction temperature was controlledbetween 45-50° C. for the duration of addition. Addition oftriethylsilane was complete in 1 hour. The batch color became greenishbrown at completion. The batch was stirred for three more hours at 40°C., then allowed to cool. When the batch temperature reached ca. 30° C.,product started to crystallize. The batch was further cooled to 1-2° C.in a water/ice bath, and after stirring for another half hour at 1-2°C., the slurry was filtered. The crystalline solid was washed with two60 mL portions of hexane, the first as a displacement wash and thesecond as a reslurry on the filter. The solids were vacuum filtereduntil dry on the filter under a stream of nitrogen and the solids werethen transferred to a clean container. A total of 49.9 grams of materialwas isolated. Mp 87.5-90.5° C. and HNMR identical with known samples of33. GC (HP-5 25 meter column, 1 mL N₂/min at 100° C., FID detection at300° C., split 50:1) of the product showed homogeneous material. Theisolated yield was 88% of 33.

EXAMPLE 2 Preparation of 2,2-dibutyl-1,3-propanediol, 54

[0314]

[0315] (This method is similar to that described in U.S. Pat. No.5,994,391, Example Corresponding to Scheme XI, Step 1, column 264.)Lithium aluminum hydride (662 ml, 1.2 equivalents, 0.66 mol) in 662 mLof IM THF was added dropwise to a stirred solution ofdibutyl-diethylmalonate (150 g, 0.55 mol) (Aldrich) in dry THF (700 ml)while maintaining the temperature of the reaction mixture at betweenabout −20?C to about 0?C using an acetone/dry ice bath. The reactionmixture was then stirred at room temperature overnight. The reaction wascooled to −20?C and 40 ml of water, 80 ml of 10% NaOH and 80 ml of waterwere successively added dropwise. The resulting suspension was filtered.The filtrate was dried over sodium sulfate and concentrated under vacuumto give 98.4 g (yield 95%) of the diol as an oil. Proton NMR, carbon NMRand MS confirmed the product.

[0316] Alternate reducing agents that will be useful in this preparationof compound 54 include diisobutylaluminum hydride (DIBAL-H) or sodiumbis(2-methoxyethyxy)aluminum hydride (for example, Red-Al supplied byAldrich).

EXAMPLE 3 Preparation of 1-bromo-2-butyl-2-(hydroxymethyl)hexane, 52

[0317]

[0318] A 250 mL 3-necked round-bottomed flask was fitted with amechanical stirrer, a nitrogen inlet, an addition funnel or condenser ordistilling head with receiver, a thermocouple connected to a J-Kemtemperature controller and a thermocouple connected to analog dataacquisition software, and a heating mantle. The flask was purged withnitrogen and charged with 20 grams of 54. To this was added 57 grams ofa 30 wt. % solution of HBr in acetic acid. The mixture was heated to 80°C. for 4 hrs. The solvents were distilled off to a pot temperature of125° C. over 20 minutes. This removes most of the residual HBr. Themixture was cooled to 80° C. and 100 mL of Ethanol 2B (source: Aaper)was added at once. Next 1.0 mL of concentrated sulfuric acid was added.The solvent was distilled off (10 to 15 ml solvent at 79-80° C.). Andthe mixture was refluxed for 2 h. An additional 10 to 15 ml of solventwas distilled off and the mixture was again held at reflux temperaturefor 2 h. Further solvent was distilled off to a pot temperature of 125°C. and then the flask contents were cooled to 25.0° C. To the flask wasadded 100 mL of ethyl acetate and 100 mL of 2.5N sodium hydroxide. Themixture was agitated for 15 minutes and the aqueous layer was separated.Another 100 mL of water was added to the pot and the contents wereagitated 15 minutes. The aqueous layer was separated and solvent wasdistilled off to a pot temperature of 125° C. During this process wateris removed by azeotropic distillation with ethyl acetate. The productwas concentrated under reduced pressure to afford 26.8 g of a brown oilcontaining the product 52 (96.81% by GC: HP1 column; initial temp. 50°C., hold for 2.5 min, Ramp 10° C./min to ending temp. 275° C., finaltime 15 min).

Example 3a Alternate Preparation of1-bromo-2-butyl-2-(hydroxymethyl)hexane, 52

[0319] A 250 mL 3-necked round-bottomed flask is fitted with amechanical stirrer, a nitrogen inlet, an addition funnel or condenser ordistilling head with receiver, a thermocouple connected to a J-Kemtemperature controller and a thermocouple connected to analog dataacquisition software, and a heating mantle. The flask is purged withnitrogen and charged with 20 grams of 54. To this is added 57 grams of a30 wt. % solution of HBr in acetic acid. The mixture is heated to 80° C.for 4 hrs. The solvents are vacuum distilled off to a pot temperature of90° C. over 20 minutes. This removes most of the residual HBr. Themixture is cooled to 80° C. and 100 mL of Ethanol 2B (source: Aaper) isadded at once. Next 1.0 mL of concentrated sulfuric acid is added. Thesolvent is distilled off (10 to 15 ml solvent at 79-80° C.). And themixture is refluxed for 2 h. An additional 10 to 15 ml of solvent isdistilled off and the mixture is again held at reflux temperature for 2h. Further solvent is distilled off to a pot temperature of 85° C. andthen the flask contents are cooled to 25.0° C. To the flask is added 100mL of ethyl acetate and 100 mL of 2.5N sodium hydroxide. The mixture isagitated for 15 minutes and the aqueous layer is separated. Another 100mL of water is added to the pot and the contents are agitated 15minutes. The aqueous layer is separated and solvent is distilled off toa pot temperature of 85° C. During this process water is removed byazeotropic distillation with ethyl acetate. The material is concentratedunder reduced pressure to afford the product 52.

EXAMPLE 4 Preparation of 2-(bromomethyl)-2-butylhexanal, 53

[0320]

[0321] A 500 mL 3-necked round-bottom flask was fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple connected to a J-Kem temperaturecontroller and a thermocouple connected to analog data acquisitionsoftware, and a heating mantle. The flask was purged with nitrogen gasand charged with 26.0 grams of 52 and 15.6 grams of triethylamine. In a250 ml flask was slurried 37.6 grams of sulfur trioxide-pyridine in 50mL of DMSO. The DMSO slurry was added to the round-bottom flask byaddition funnel over 15 min. The addition temperature started at 22° C.and reached a maximum of 41.0° C. (Addition of the slurry attemperatures below 18.0° C. will result in a very slow reaction,building up sulfur trioxide with will react rapidly when the temperaturerises above 25° C.) The mixture was stirred for 15 minutes. To themixture was added 100 mL of 2.5M HCl over 5 minutes. The temperature wasmaintained below 35° C. Next, 100 mL of ethyl acetate was added and themixture was stirred 15 minutes. The mixture was then cooled to ambientand the aqueous layer was separated. To the pot was added 100 mL ofwater and the mixture was agitated for 15 minutes. The aqueous layer wasseparated. The solvent was distilled to a pot temperature of 115° C. andthe remaining material was concentrated under reduce pressure to afford21.8 g of a brown oil containing the product 53 (95.1% by GC: HP1column; initial temp. 50° C., hold for 2.5 min, Ramp 10° C./min toending temp. 275° C., final time 15 min).

Example 4a Alternate Preparation and Purification of2-(Bromomethyl)-2-butylhexanal, 53

[0322] a. Preparation of Compound 52

[0323] To the reactor is charged 2,2-dibutyl-1,3-propanediol followed by30 wt % HBr in acetic acid. The vessel is sealed and heated at aninternal temperature of ca. 80° C. and held for a period of ca. 7 hours,pressure maintained below 25 psia. A GC of the reaction mixture is takento determine reaction completion (i.e., conversion of2,2-dibutyl-1,3-propanediol into 3-acetoxy-2,2-dibutyl-1-propanol). Ifthe reaction is not complete at this point, the mixture may be heatedfor an additional period of time to complete the conversion. Aceticacid/HBr is then removed using house vacuum (ca. 25 mmHg) up to amaximum internal temperature of ca. 90° C. Ethanol is then addedfollowed by sulfuric acid. A portion of the ethanol is removed (ca.one-quarter of the ethanol added) via atmospheric distillation. Ethanolis then added back (ca. the amount removed during the distillation) tothe reactor containing the 3-acetoxy-2,2-dibutyl-1propanol and thecontents are heated to reflux (ca. 80° C. with a jacket temperature of95° C.) and then held at reflux for ca. 8 hours. Ethanol is then removedvia atmospheric distillation up to a maximum internal temperature of 85°C., using a jacket temperature of 95° C. A GC is taken to determinereaction completion (i.e., conversion of3-acetoxy-2,2-dibutyl-1-propanol to compound 52). If the reaction is notcomplete, ethanol is added back to the reactor and the contents areheated to reflux and then held at reflux for an additional 4 hours (ca.80° C., with a jacket of 95° C.). Ethanol is then removed viaatmospheric distillation up to a maximum internal temperature of 85° C.,using a jacket temperature of 95° C. A GC is taken to determine reactioncompletion (i.e., conversion of 3-acetoxy-2,2-dibutyl-1-propanol tocompound 52). Once the reaction is deemed to be complete, the remainingethanol is removed via atmospheric distillation up to a maximum internaltemperature of 125° C. Methyl t-butyl ether is then added followed by a5% sodium bicarbonate solution. The layers are separated, the aqueouslayer is extracted once with MTBE, the organic extracts-are combined,washed once with water, dried over MgSO₄, and concentrated under housevacuum (ca. 25 mmHg) to a maximum internal temperature of 60° C. Theresultant oil is stored in the cooler until it is needed for furtherprocessing.

[0324] b. Preparation of Compound 53.

[0325] Methyl sulfoxide is charged to the reactor followed by compound52 and triethylamine. Pyridine-sulfur trioxide complex is then addedportion-wise to the reactor while maintaining an internal temperature of<35° C. Once the pyridine-sulfur trioxide complex addition is complete,a GC of the reaction mixture is taken to determine reaction completion(i.e., conversion of 52 into 53). If the reaction is not complete atthis point, the mixture may be stirred for an additional period of timeto complete the conversion. The reaction is quenched with an 11 wt %aqueous HCl solution. Ethyl acetate is added and the layers areseparated, the aqueous layer is extracted once with ethyl acetate, theorganic extracts are combined, washed once with water, dried over MgSO₄,and concentrated under house vacuum (ca. 25 mm/Hg) to a maximum internaltemperature of 30° C. The resultant oil is stored in the cooler until itis needed for further processing.

[0326] c. Alternate Preparation of Compound 53.

[0327] Compound 52 and methylene chloride are charged to the reactorfollowed by TEMPO. The solution is cooled to ca. 0-5° C. Potassiumbromide and sodium bicarbonate are dissolved in a separate reactor andadded to the solution of 52 and TEMPO at 0-5° C. The biphasic mixture iscooled to 0-5° C. and sodium hypochlorite is added at such a rate tomaintain an internal temperature of 0-5° C. When the add is complete aGC of the reaction mixture is performed to determine reactioncompletion. If the reaction is not complete (>1% 52 remaining),additional sodium hypochlorite may be added to drive the reaction tocompletion. Immediately after the reaction is determined to be complete,an aqueous solution of sodium sulfite is added to quench the remainingsodium hypochlorite. The layers are separated, the aqueous layer isback-extracted with methylene chloride, the combined organic fractionsare washed and dried over sodium sulfate. Compound 53 is thenconcentrated via a vacuum distillation, up to a maximum internaltemperature of ca. 30° C. The crude aldehyde is stored in the cooleruntil it is required for further processing.

[0328] d. Purification of Compound 53.

[0329] A Wiped Film Evaporated (WFE) apparatus is set up with thefollowing conditions: evaporator temperature of 90° C., vacuum of ca.0.2 mmHg and a wiper speed of 800 rpm's. The crude compound 53 is fed ata rate of 1.0-1.5 kilograms of crude per hour. The approximate ratio ofproduct to residue during distillation is 90:10.

EXAMPLE 5 Preparation of1-(2,2-dibutyl-S,S-dioxido-3-oxopropylthio)-2-((4methoxyphenyl)methyl)-4-nitrobenzene,30

[0330]

[0331] A 1000 mL 4 neck jacketed Ace flask was fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple, four internal baffles and a 28 mmTeflon turbine agitator. The flask was purged with nitrogen and chargedwith 75.0 grams of 33. Next, the flask was charged with 315.0 grams ofdimethylacetamide (DMAC), agitation was started and the mixture washeated to 30° C. Sodium sulfide (39.2 grams) was dissolved in 90 mlwater in a separate flask. The aqueous sodium sulfide solution wascharged into the flask over a 25 minute period. Temperature reached 37°C. at completion of addition. The solution turned dark red immediatelyand appeared to form a small amount of foam-like globules that adheredto the wall of the reactor. The temperature was held for two hrs at 40°C. To the flask was charged 77.9 grams of 53 all at once. The reactionmixture was heated to 65° C. and held for 2 hrs. Next 270 ml water wasadded at 65° C. The mixture was agitated 15 minutes. To the flask wasthen charge 315 ml of benzotrifluoride and the mixture was agitated 15minutes. The aqueous layer was separated at 50° C. The organic layer waswashed with 315 ml of 3% sodium chloride solution. The aqueous layer wasseparated at 50° C. The solvent was distilled to a pot temperature of63° C. at 195 to 200 mmHg. The flask contents were cooled to 60° C. andto it was charged 87.7 grams of trimethyl orthoformate, and 5.2 grams ofp-toluenesulfonic acid dissolved in 164.1 mL of methanol. The mixturewas heated to reflux, 60 to 65° C. for 2 hours. The solvent wasdistilled to a pot temperature of 63° C. at 195 to 200 mmHg to removemethanol and methylformate. The flask was then charged with 252 mlbenzotrifluoride and then cooled to 15° C. Next 22.2 grams sodiumacetate as a slurry in 30 ml water was added to the flask. The flask wasthen charged with 256.7 grams of commercial peracetic acid (nominally30-35% assay) over 20 minutes, starting at 15° C. and allowing theexotherm to reach 30 to 35° C. The addition was slow at first to controlinitial exotherm. After the first equivalent was charged the exothermsubsided. The mixture was heated to 30° C. and held for 3 hours. Theaqueous layer was separated at 30° C. The organic layer was washed with315 ml 6% sodium sulfite. The aqueous layer was separated. The flask wasthen charged with 40% by wt. sulfuric acid and heated to 75° C. for 2hrs. The aqueous layer was separated from the bottom at 40 to 50° C. Tothe flask was added 315 ml saturated sodium bicarbonate and the contentswere stirred for 15 minutes. The aqueous layer was separated. Thesolvent was distilled to a reactor temperature of 63° C. at 195 to 200mmHg. Next, 600 ml isopropyl alcohol was charged over 10 minutes and thetemperature was maintained at 50° C. The reactor was cooled to 38° C.and held for 1 hour. (The product may oil slightly at first thencrystallize during the hold period. If product oils out at 38° C. ordoes not crystallize it should be seeded to promote crystallizationbefore cooling.) The reactor was cooled to 15° C. over 30 minutes thenheld for 60 minutes. The solids were filtered and dried to yield 102.1grams of a crystalline yellow solid. Wash with 150 ml 10° C. IPA.Analysis by HPLC (Zorbax RX-C8 column, 0.1% aq. TFA/acetonitrilegradient mobile phase, UV detection at 225 nm) showed 97.7% by weight of30, 79.4% isolated molar corrected yield.

Example 5a Alternate Preparation of1-(2,2-dibutyl-S,S-dioxido-3-oxopropylthio)-2-((4methoxyphenyl)methyl)-4-nitrobenzene,30

[0332] Step 1. Preparation of Sulfide Aldehyde Compound 69.

[0333] A 1000 mL 4 neck jacketed Ace reator is fitted with a mechanicalstirrer, nitrogen inlet, additional funnel, a thermocouple, fourinternal baffles, and a 28 mm Teflon turbine agitator. The flask ispurged with nitrogen gas and charged with 145 g of compound 33 and 609mL of N,N-dimethylacetamide (DMAC). Agitation is started and the mixtureis heated to 30° C. In a separate flask 72.3 g of Na₂S (Spectrum) isdissolved in 166.3 mL of water. The aqueous Na₂S is charged to the flaskover a period of about 90 minutes. Addition rate should be adjusted tomaintain the reaction temperature below 35° C. The mixture is stirred at35° C. for 2 hours and then 150.7 g of compound 53 is added all at once.The mixture is heated to 70° C. and held for 2 hours. To the mixture isadjusted to 50° C., to it is added 442.7 mL water and the mixture isagitated for 15 minutes. To the reactor is then charged 609 mL ofbenzotrifluoride followed by 15 minutes of agitation. The aqueous layeris separated at 50° C. The organic layer is washed with 3% aq. NaCl. Theaqueous layer is separated at 50° C. The organic layer contains compound69. The organic layer is stable and can be held indefinitely.

[0334] Step 2. Preparation of Compound 70.

[0335] The solvent is distilled at about 63° C. to 66° C. and 195 to 200mmHg from the organic layer resulting from Step 1 until a third to ahalf of the benzotrifluoride volume is distilled. The mixture is cooledto about 60° C. and charged with 169.6 g of trimethylorthoformate andabout 10 g of p-toluenesulfonic acid dissolved in 317.2 mL of methanol.(Note: alternate orthoformates, for example triethylorthoformate, can beused in place of trimethylorthoformate to obtain other acetals.) Thereactor is fitted with a condenser and a distillation head. The mixtureis heated to boiling and from it is distilled 5 mL of methanol to removeresidual water from the condenser and the mixture is held at reflux at60° C. to 65° C. for about 2 hours. Solvent is then distilled to a pottemperature of 60° C. to 66° C. at 195 to 200 mm Hg to remove methanoland methylformate. To the mixture is added 355.4 mL benzotrifluoride andthe mixture is cooled to 15° C. To the reactor is charged 32.1 g sodiumacetate slurried in 77.2 mL water. The reaction is held for 72 hours. Tothe reactor is then charged 340.4 g of peracetic acid over a 2 hourperiod starting at 15° C. Addition was adjusted to keep the temperatureat or below 20° C. The mixture was then heated to 25° C. for 4 hours.The aqueous (top) layer was separated at 25° C. and the organic layerwas washed with 190 mL of 10% sodium sulfite. The organic layer containscompound 70 and can be stored indefinitely.

[0336] Step 3. Preparation of Compound 30.

[0337] To the organic layer of Step 2 is added 383.8 g of concentratedsulfuric acid. The mixture is heated at 75° C. for 2 hours and theaqueous (bottom) layer is separated at 40 to 50° C. To the reactor ischarged 609 mL of 10% sodium bicarbonate and the mixture is stirred for15 minutes. The aqueous (top) layer is separated. Solvent is distilledfrom the organic layer at 63 to 66° C. at 195 to 200 mm Hg. To thereactor is charged 1160 mL of isopropyl alcohol over 10 minutes at 50°C. The reactor is cooled to 38° C. and held for 1 hour. Somecrystallization occurs. The reactor is cooled to 15° C. over 30 minutesand held for 120 minutes, causing further crystallization of 30. Thecrystals are filtered and dried to yield 200.0 g of a crystalline yellowsolid. The crystals of 30 are washed with 290 mL of 10° C. isopropylalcohol.

EXAMPLE 6 Preparation of1-(2,2-dibutyl-S,S-dioxido-3-oxopropylthio)-2-((4methoxyphenyl)methyl)-4-dimethylaminobenzene,29

[0338]

[0339] A 300 ml autoclave was fitted with a Stirmix hollow shaft gasmixing agitator, an automatic cooling and heating temperature control,and an in-reactor sampling line with sintered metal filter. At 20° C.the autoclave was charged with 15.0 grams of 30, 2.5 grams of Pd/Ccatalyst, 60 grams of ethanol, 10.0 grams of formaldehyde (36% aqueoussolution), and 0.55 grams of concentrated sulfuric acid. The reactor wasclosed and pressurized the reactor to 60 psig (515 kPa) with nitrogen tocheck for leakage. The pressure was then reduced to 1-2 psig (108-115kPa). The purge was repeated three times. The autoclave was thenpressurized with H₂ to 60 psig (515 kPa) while the reactor temperaturewas held at 22° C. The agitator was started and set to 800-1000 rpm andthe reactor temperature control is set at 30-40° C. When the coolingcapacity was not enough to control the temperature, the agitator rpm orthe reactor pressure was reduced to maintain the set temperature. Afterabout 45 minutes when the heat release was slowing down (about 70% ofhydrogen usage was reacted), the temperature was raised to 60° C.Hydrogen was then released and the autoclave was purged with nitrogenthree times. The content of the reactor was pressure filtered through asintered metal filter at 60° C. The filtrate was stirred to cool to theroom temperature over 1-2 hours and 50 grams of water was added over 1hour. The mixture was stirred slowly at 4° C. overnight and filteredthrough a Buche type filter. The cake was air dried to give 13.0 gramsof 29 with 99+% assay. The isolated yield was 89%.

EXAMPLE 7 5 Preparation ofsyn-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,syn-24

[0340]

[0341] A 250 ml round bottom glass reactor fitted with mechanicalagitator and a heating/cooling bath was purged with nitrogen. Forty-fivegrams of potassium t-butoxide/THF solution were charged to the reactorand agitation was started. In a separate container 18 grams of 29 wasdissolved in 25 grams of THF. The 29/THF solution was charged into thereactor through a addition funnel over about 2.0 hours. The reactortemperature was controlled between about 16-20° C. Salt precipitatedafter about half of 29 was added. The slurry was stirred at 16-20° C.for an hour. The reaction was quenched with 54 grams of 7.4% ammoniumchloride aqueous solution over a period of about 30 minutes whilekeeping the reactor temperature at 16-24° C. The mixture was gentlystirred until all salt is dissolved (about 10 minutes). Agitation wasstopped and the phases were allowed to separate. The aqueous layer wasdrained. The organic layer was charged with 50 ml water and 25 grams ofisopropyl alcohol. The agitator was started and crystallization wasallowed to take place. The THF was distilled under the ambient pressure,with b.p. from 60 to 65° C. and pot temperature from 70 to 77° C. Thecrystals dissolved as the pot gets heated and reappeared when the THFstarted to distill. After distillation was complete, the slurry wasslowly cooled to 4° C. over 2-3 hours and stirred slowly for severalhours. The slurry was filtered with a 150 ml Buche filter and the cakewas washed with 10 grams of cold 2:1 water/isopropyl alcohol solution.Filtration was complete in about 5 minutes. The cake was air dried togive 16.7 grams of syn-24 with 99+% assay and a 50/50 mixture of R,R andS,S isomers.

EXAMPLE 8a. Conditions for Optical Resolution of Compound (4R,5R)-24

[0342]

[0343] The following simulated moving bed chromatography (SMB)conditions are used to separate the (4R,5R) and (4S,5S) enantiomers ofcompound syn-24. Column (CSP): Daicel Chiralpak AS Mobile Phase:acetonitrile (100%) Column Length: 11 cm (9 cm for column 6) ColumnI.D.: 20.2 cm Number of Columns: 6 columns Feed Concentration: 39grams/liter Eluent Flowrate: 182 L/hour Feed Flowrate: 55 L/hour ExtractFlowrate: 129.4 L/hour Raffinate Flowrate: 107.8 L/hour RecyclingFlowrate: 480.3 L/hour Period: 0.6 minute Temperature: ambient

[0344] SMB Performance:

[0345] Less retained enantiomer purity (%): 92.8%

[0346] Less retained enantiomer concentration: 10 g/L

[0347] More retained enantiomer recovery yield (%): 99.3%

[0348] More retained enantiomer concentration: 7 g/L

Example 8b Alternate Conditions for Optical Resolution of Compound(4R,5R)-24

[0349] The following simulated moving bed chromatography (SMB)conditions are used to separate the (4R,5R) and (4S,5S) enantiomers ofcompound syn-24. Column (CSP): di-methyl phenyl derivative of tartaricacid (Kromasil DMB) Mobile Phase: toluene/methyl tert-butyl ether(70/30) Column Length: 6.5 cm Column I.D.: 2.12 cm Number of Columns: 8columns Zones: 2-3-2-1 Feed Concentration: 6.4 weight percent EluentFlowrate: 20.3 g/minute Feed Flowrate: 0.7 g/minute Extract Flowrate:5.0 g/minute Raffinate Flowrate: 16.0 g/minute Period: 8 minuteTemperature: ambient

[0350] SMB Performance:

[0351] Less retained enantiomer purity (%): >98%

[0352] Less retained enantiomer recovery yield (%): >95%

Example 8c Alternate Conditions for Optical Resolution of Compound(4R,5R)-24

[0353] The following simulated moving bed chromatography (SMB)conditions are used to separate the (4R,5R) and (4S,5S) enantiomers ofcompound syn-24. di-methyl phenyl derivative of tartaric Column (CSP):acid (Kromasil DM3) Mobile Phase: toluene (100%) Column Length: 6.5 cmColumn I.D.: 2.12 cm Number of Columns: 8 columns Zones: 2-3-2-1 FeedConcentration: 64 weight percent Eluent Flowrate: 20.3 g/minute FeedFlowrate:  0.5 g/minute Extract Flowrate:  4.9 g/minute RaffinateFlowrate: 15.9 g/minute Period: 8 minute Temperature: ambient

[0354] SMB Performance:

[0355] Less retained enantiomer purity (%): >98%

[0356] Less retained enantiomer recovery yield (%): >95%

Example 8d Racemization of Compound (4S,5S)-24

[0357]

[0358] A 250 mL round bottom glass reactor with mechanical agitator anda heating/cooling bath is purged with nitrogen gas. In a flask, 18 g of(4S,5S)-24 (obtained as the more retained enantiomer in Examples 8a-8c)is dissolved in 50 g of dry THF. This solution is charged into thereactor and brought to about 23-25° C. with agitation. To the reactor ischarged 45 g of potassium t-butoxide/THF solution (1 M, Aldrich) throughan addition funnel over about 0.5 hour. A slurry forms. Stir the slurryat about 24-26° C. for about 1-1.5 hours. The reaction is quenched with54 g of 7.5% aqueous ammonium chloride while keeping the reactortemperature at about 23-26° C. The first ca. 20% of the ammoniumchloride solution is charged slowly until the slurry turns thin and therest of the ammonium chloride solution is charged over about 0.5 hour.The mixture is stirred gently until all the salt is dissolved. Theagitation is stopped and the phases are allowed to separate. The aqueouslayer is removed. To the organic layer is charged 50 mL of water and 25g of isopropyl alcohol. The agitator is started and crystallization isallowed to take place. THF is removed by distillation at ambientpressure. The crystals dissolve as the pot warms and then reappear whenthe THF starts to distill. The resulting slurry is cooled slowly to 4°C. within 2-3 hours and slowly stirred for 1-2 hours. The slurry isfiltered with a 150 mL Buche filter and washed with 20 g of 04° C.isopropyl alcohol. The cake is air dried at about 50-60° C. under vacuumto give 16.7 g of racemic 24.

EXAMPLE 9 Preparation of(4R,5R)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,(4R,5R)-28

[0359]

[0360] A 1000 mL 4 neck Reliance jacketed reactor flask was fitted witha mechanical stirrer, a nitrogen inlet, an addition funnel, condenser ordistillation head with receiver, a thermocouple, and a Teflon paddleagitator. The flask was purged with nitrogen gas and was charged with41.3 grams of (4R,5R)-24 and 18.7 grams of methionine followed by 240grams of methanesulfonic acid. The mixture was heated to 75° C. andstirred for 8 hrs. The mixture was then cooled to 25° C. and chargedwith 480 mL of 3-pentanone. The solution was homogeneous. Next, theflask was charged with 320 mL of dilution water and was stirred for 15minutes. The aqueous layer was separated and to the organic layer wasadded 250 mL of saturated sodium bicarbonate. The mixture was stirredfor 15 minutes and the aqueous layer was separated. Solvent wasdistilled to approximately one-half volume under vacuum at 50° C. Theflask was charged with 480 mL of toluene, forming a clear solution.Approximately half the volume of solvent was removed at 100 mmHg. Themixture was cooled to 10° C. and stirred overnight. Crystals werefiltered and washed with 150 mL cold toluene and allowed to dry undervacuum. Yielded 29.9g with a 96.4 wt % assay. The filtrate wasconcentrated and toluene was added to give a second crop of 2.5 grams ofcrystals. A total of 32.1 g of dry off white crystalline (4R,5R)-28 wasobtained.

Example 9a Alternate Preparation of(4R,5R)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,(4R,5R)-28

[0361] A 1000 mL 4 neck Ace jacketed reactor flask is fitted with amechanical stirrer, a nitrogen inlet, an addition funnel, condenser ordistillation head with receiver, a thermocouple, and a Teflon paddleagitator. The flask is purged with nitrogen gas and is charged with 40.0grams of (4R,5R)-24 and 17.8 grams of methionine followed by 178.6 gramsof methanesulfonic acid. The mixture is heated to 80° C. and stirred for12 hrs. The mixture is then cooled to 15° C. and charged with 241.1 mLof water over 30 minutes. The reactor is then charged with 361.7 mL of3-pentanone. Next, the flask is stirred for 15 minutes. The aqueouslayer is separated and to the organic layer is added 361.7 mL ofsaturated sodium bicarbonate. The mixture is stirred for 15 minutes andthe aqueous layer was separated. Solvent is distilled to approximatelyone-half volume under vacuum at 50° C. Crystals start to form at thistime. The flask is charged with 361.7 mL of toluene and the mixture iscooled to 0° C. Crystals are allowed to form. Crystals are filtered andwashed with 150 mL cold toluene and allowed to dry under vacuum at 50°C. Yield 34.1 g of off-white crystalline (4R,5R)-28.

Example 9b Alternate Preparation of(4R,5R)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,(4R,5R)-28

[0362] A first 45 L reactor is purged with nitrogen gas. To it ischarged 2.5 kg of (4R,5R)-24 followed by 1.1 kg of methionine and 11.1kg of methanesulfonic acid. The reaction mixture is heated to 85° C.with agitation for 7 hours. The reaction mixture is then cooled to 5° C.and 17.5 L of water is slowly charged to the first reactor. The reactiontemperature will reach about 57° C. Next, 17.5 L of methyl isobutylketone (MIBK) are charged to the first reactor and the reaction mixtureis stirred for 30 minutes. The mixture is allowed to stand for 30minutes and the layers are separated. The aqueous phase is transferredto a second 45 L reactor and 10 L of MIBK is charged to the secondreactor. The second reactor and its contents are stirred for 30 minutesand then allowed to stand for 30 minutes while the layers separate. Theorganic phase is separated from the second reactor and the two organicphases are combined in the first reactor. To the first reactor iscarefully charged 1.4 kg of aqueous sodium bicarbonate. The mixture isstirred for 30 minutes and then allowed to stand for 30 minutes. Thephases are separated. If the pH of the aqueous phase is less than 6 thena second bicarbonate wash is performed. After the bicarbonate wash, 15 Lof water is charged to the first reactor and the mixture is heated to40° C. The mixture is stirred for 30 minutes and then allowed to standfor 30 minutes. The phases are separated. The organic phase isconcentrated by vacuum distillation so that approximately 5 L of MIBKremain in the concentrate. The distillation starts when the batchtemperature is at 35° C. at 1 psia. The distillation is complete whenthe batch temperature reaches about 47.8° C. The batch temperature isthen adjusted to 45° C. and 20 L of heptane is charged to the productmixture over 20 minutes. The resulting slurry is cooled to 20° C. Theproduct slurry is filtered (10 micron cloth filter) and washed with 8 Lof 20% MIBK/heptane solution. The product is dried on the filter at 80°C. for 21 hours under vacuum. A total of 2.16 kg of white crystalline(4R,5R)-28 is isolated.

Example 9c Batch Isolation of Compound (4R,5R)-28 (or Compound(4S,5S)-2) from Acetonitrile Solution

[0363] A 1 L reactor is equipped with baffles and a 4-blade radial flowturbine. The reactor is purged with 1L of nigrogen gas and charged with300 mL of water. The water is stirred at a minimum rate of 300 rpm at 5°C. The reactor is charged with 125-185 mL of (4R,5R)-28 in acetonitrilesolution (20% w/w) at a rate of 1.4 mL/min. Upon addition, crystalsstart to form. After addition of the acetonitrile solution, crystals arefiltered through a Buchner funnel. The cake is washed with 3 volumes ofwater and/or followed by 1-2 volumes of ice cold isopropyl alcoholbefore drying. Alternatively, this procedure can be used on anacetonitrile solution of (4S,5S)-28 to isolate (4S,5S)-28.

Example 9d Continuous Isolation of Compound (4R,5R)-28 (or Compound(4S,5S)-28) from Acetonitrile Solution

[0364] A 1 L reactor is equipped with baffles and a 4-blade radial flowturbine. The reactor is purged with 1L of nigrogen gas and charged with60 grams of water and 30 grams of acetonitrile. The mixture is stirredat 300 rpm and 5° C. Into the reactor are fed 300 mL of water and 125 mLof 20% (w/w) (4R,5R)-28 in acetonitrile solution at rates of 1.7 mL/minand 1 mL/min, respectively. When the contents of the reactor reach70-80% of the volume of the reactor, the slurry can be drained to afilter down to aminimum stirring level in the reactor and followed bymore feeding. Alternatively, the reactor can be drained continuously asthe feeds continue. The water/acetonitrile ratio can be in the range ofabout 2:1 to about 3:1. Filtered cake can be handled as described inExample 9c. Alternatively, this procedure can be used on an acetonitrilesolution of (4S,5S)-28 to isolate (4S,5S)-28.

EXAMPLE 10 Preparation of 1-(chloromethyl)-4-(hydroxymethyl)benzene, 55

[0365]

[0366] A reaction flask fitted with a nitrogen inlet and outlet, areflux condenser, and a magnetic stirrer was purged with nitrogen. Theflask was charged with 25 g of 4-(chloromethyl)benzoic acid. The flaskwas charged with 75 mL of THF at ambient temperature. Stirring caused asuspension to form. An endothermic reaction ensued in which thetemperature of the reaction mixture dropped 22° C. to 14° C. To thereaction mixture 175 mL of borane-THF adduct was added via a droppingfunnel over about 30 minutes. During this exothermic addition, anice-bath was used for external cooling to keep the temperature below 30°C. The reaction mixture was stirred at 20° C. for 1 h and it was thencooled to 0° C. The reaction mixture was quenched by slow addition of 1Msulfuric acid. The resulting reaction mixture was diluted with 150 mL oft-butyl methyl ether (TBME) and stirred for at least 20 min to destroyboric acid esters. The layers were separated and the aqueous layer waswashed with another portion of 50 mL of TBME. The combined organiclayers were washed twice with 100 mL of saturated sodium bicarbonatesolution. The organic layer was dried over 11 g of anhydrous sodiumsulfate and filtered. The solvents were evaporated on a rotaryevaporator at 45° C. (bath temperature) and <350 mbar yielding acolorless oil. The oil was seeded with crystals and the resulting solid55 was dried under vacuum. Yield: 19.7g (86%). Assay by GC (HP-5 25meter column, 1 mL N₂/min at 100° C., FID detection at 300° C., split50:1).

EXAMPLE 11 Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octaneChloride, 41

[0367]

[0368] Step 1. Preparation of (4R,5R)-26.

[0369] A 1000 mL 4 neck jacketed Ace reactor flask was fitted with amechanical stirrer, a nitrogen inlet, an addition funnel or condenser ordistilling head with receiver, a thermocouple, four internal baffles anda 28 mm Teflon turbine agitator. The flask was purged with nitrogen gasand charged with 25.0 grams of (4R,5R)-28 and 125 mL ofN,N-dimethylacetamide (DMAC). To this was added 4.2 grams of 50% sodiumhydroxide. The mixture was heated to 50° C. and stirred for 15 minutes.To the flask was added 8.3 grams of 55 dissolved in 10 mL of DMAC, allat once. The temperature was held at 50° C. for 24 hrs. To the flask wasadded 250 mL of toluene followed by 125 mL of dilution water. Themixture was stirred for 15 minutes and the layers were then allowed toseparate at 50° C. The flask was then charged with 125 mL of saturatedsodium chloride solution and stirred 15 minutes. Layers separatedcleanly in 30 seconds at 50° C. Approximately half of the solvent wasdistilled off under vacuum at 50° C. The residual reaction mixturecontained (4R,5R)-26.

[0370] Step 2. Preparation of (4R,5R)-27.

[0371] Toluene was charged back to the reaction mixture of Step 1 andthe mixture was cooled to 35° C. To the mixture was then added 7.0 gramsof thionyl chloride over 5 minutes. The reaction was exothermic andreached 39° C. The reaction turned cloudy on first addition of thionylchloride, partially cleared then finally remained cloudy. The mixturewas stirred for 0.5 hr and was then washed with 0.25N NaOH. The mixtureappeared to form a small amount of solids that diminished on stirring,and the layers cleanly separated. The solvent was distilled to a minimumstir volume under vacuum at 50° C. The residual reaction mixturecontained (4R,5R)-27.

[0372] Step 3. Preparation of 41.

[0373] To the reaction mixture of Step 2 was charged with 350 mL ofmethyl ethyl ketone (MEK) followed by 10.5 mL water and 6.4 grams ofdiazabicyclo[2.2.2]octane (DABCO) dissolved in 10 mL of MEK. The mixturewas heated to reflux, and HPLC showed <0.5% of (4R,5R)-27. The reactionremained homogenous initially then crystallized at the completion of thereaction. An additional 5.3 mL of water was charged to the flask toredissolve product. Approximately 160 mL of solvent was then distilledoff at atmospheric pressure. The mixture started to form crystals after70 mL of solvent was distilled. Water separated out of distillateindicating a ternary azeotrope between toluene, water and methyl ethylketone (MEK). The mixture was then cooled to 25° C. The solids werefiltered and washed with 150 mL MEK, and let dry under vacuum at 60° C.Isolated 29.8.0 g of off-white crystalline 41.

Example 11a Alternate Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octaneChloride, Form II of 41

[0374] A 1000 mL 4 neck jacketed Ace reactor flask is fitted with amechanical stirrer, a nitrogen inlet, an addition funnel or condenser ordistilling head with receiver, a thermocouple, four internal baffles anda 28 mm Teflon turbine agitator. The flask is purged with nitrogen gasand charged with 25.0 grams of (4R,5R)-28 and 100 mL ofN,N-dimethylacetamide (DMAC). The mixture is heated to 50° C. and to itis added 4.02 grams of 50% sodium hydroxide. The mixture is stirred for30 minutes. To the flask is added 8.7 grams of 55 dissolved in 12.5 mLof DMAC, all at once. The charge vessel is washed with 12.5 mL DMAC andthe wash is added to the reactor. The reactor is stirred for 3 hours. Tothe reactor is added 0.19 mL of 49.4% aq. NaOH and the mixture isstirred for 2 hours. To the mixture is added 0.9 g DABCO dissolved in12.5 mL DMAC. The mixture is stirred 30 to 60 minutes at 50° C. To theflask is added 225 mL of toluene followed by 125 mL of dilution water.The mixture is stirred for 15 minutes and the layers are then allowed toseparate at 50° C. The bottom aqueous layer is removed but any rag layeris retained. The flask is then charged with 175 mL of 5% hydrochloricacid solution and stirred 15 minutes. Layers are separated at 50° C. toremove the bottom aqueous layer, discarding any rag layer with theaqueous layer. Approximately half of the solvent is distilled off undervacuum at a maximum pot temperature of 80° C. The residual reactionmixture contains (4R,5R)-26.

[0375] Step 2. Preparation of (4R,5R)-27.

[0376] Toluene (225 mL) is charged back to the reaction mixture of Step1 and the mixture is cooled to 30° C. To the mixture is then added 6.7grams of thionyl chloride over 30 to 45 minutes. The temperature ismaintained below 35° C. The reaction turns cloudy on first addition ofthionyl chloride, then at about 30 minutes the layers go back togetherand form a clear mixture. The mixture is stirred for 0.5 hr and is thencharged with 156.6 mL of 4% NaOH wash over a 30 minute period. Theaddition of the wash is stopped when the pH of the mixture reaches 8.0to 10.0. The bottom aqueous layer is removed at 30° C. and any rag layeris retained with the organic layer. To the mixture is charged 175 mL ofsaturated NaCl wash with agitation. The layers are separated at 30° C.and the bottom aqueous layer is removed, discarding any rag layer withthe aqueous layer. The solvent is distilled to a minimum stir volumeunder vacuum at 80° C. The residual reaction mixture contains(4R,5R)-27.

[0377] Step 3. Preparation of 41.

[0378] To the reaction mixture of Step 2 is charged 325 mL of methylethyl ketone (MEK) and 13 mL water. Next, the reactor is charged 6.2grams of diazabicyclo[2.2.2]octane (DABCO) dissolved in 25 mL of MEK.The mixture is heated to reflux and held for 30 minutes. Approximately10% of solvent volume is then distilled off. The mixture starts to formcrystals during distillation. The mixture is then cooled to 20° C. for 1hour. The off-white crystalline 41 (Form II) is filtered and washed with50 mL MEK, and let dry under vacuum at 100° C.

Example 11b Alternate Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octaneChloride, Form II of 41

[0379] A 1000 mL 4 neck jacketed Ace reactor flask is fitted with amechanical stirrer, a nitrogen inlet, an addition funnel or condenser ordistilling head with receiver, a thermocouple, four internal baffles anda Teflon turbine agitator. The flask is purged with nitrogen gas andcharged with 25.0 grams of (4R,5R)-28 and 125 mL ofN,N-dimethylacetamide (DMAC). The mixture is heated to 50° C. and to itis added 7.11 grams of 30% sodium hydroxide over a period of 15 to 30minutes with agitation. The mixture is stirred for 30 minutes. To theflask is added 9.5 grams of solid 55. The reactor is stirred for 3hours. To the mixture is added 1.2 g of solid DABCO. The mixture isstirred 30 to 60 minutes at 50° C. To the flask is added 225 mL oftoluene followed by 125 mL of water. The mixture is stirred for 15minutes and the layers are then allowed to separate at 50° C. The bottomaqueous layer is removed but any rag layer is retained with the organiclayer. The flask is then charged with 175 mL of 5% hydrochloric acidsolution and-stirred 15 minutes. Layers are separated at 50° C. toremove the bottom aqueous layer, discarding any rag layer with theaqueous layer. The flask is then charged with 225 mL of water andstirred 15 minutes. The layers are allowed to separate at 50° C. Thebottom aqueous layer is removed, discarding any rag layer with theaqueous layer. Approximately half of the solvent is distilled off undervacuum at a maximum pot temperature of 80° C. The residual reactionmixture contains (4R,5R)-26.

[0380] Step 2. Preparation of (4R,5R)-27.

[0381] Toluene (112.5 mL) is charged back to the reaction mixture ofStep 1 and the mixture is cooled to 25° C. To the mixture is then added7.3 grams of thionyl chloride over 15 to 45 minutes. The temperature ofthe mixture is maintained above 20° C. and below 40° C. The reactionturns cloudy on first addition of thionyl chloride, then at about 30minutes the layers go back together and form a clear mixture. Themixture is then charged with 179.5 mL of 4% NaOH wash over a 30 minuteperiod. The mixture is maintained above 20° C. and below 40° C. duringthis time. The addition of the wash is stopped when the pH of themixture reaches 8.0 to 10.0. The mixture is then allowed to separate at40° C. for at least one hour. The bottom aqueous layer is removed andany rag layer is retained with the organic layer. To the mixture ischarged 200 mL of dilution water. The mixture is stirred for 15 minutesand then allowed to separate at 40° C. for at least one hour. The bottomaqueous layer is removed, discarding any rag layer with the aqueouslayer. The solvent is distilled to a minimum stir volume under vacuum at80° C. The residual reaction mixture contains (4R,5R)-27.

[0382] Step 3. Preparation of 41.

[0383] To the reaction mixture of Step 2 is charged 350 mL of methylethyl ketone (MEK) and 7 mL water. The mixture is stirred for 15 minutesand the temperature of the mixture is adjusted to 25° C. Next, thereactor is charged with 6.7 grams of solid diazabicyclo[2.2.2]octane(DABCO). The mixture is maintained at 25° C. for three to four hours. Itis then heated to 65° C. and maintained at that temperature for 30minutes. The mixture is then cooled to 25° C. for 1 hour. The off-whitecrystalline 41 (Form II) is filtered and washed with 50 mL MEK, and letdry under vacuum at 100° C.

EXAMPLE 12 Alternate Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octaneChloride, Form I of 41

[0384] (4R,5R)-27 (2.82 kg dry basis, 4.7 mol) was dissolved in MTBE(9.4 L). The solution of (4R,5R)-27 was passed through a 0.2 mm filtercartridge into the feeding vessel. The flask and was rinsed with MTBE(2×2.5 L). The obtained solution as passed through the cartridge filterand added to the solution of (4R,5R)-27 in the feeding vessel. DABCO(diazabicyclo[2.2.2]octane, 0.784 kg, 7.0 mol) was dissolved in MeOH(14.2 L). The DABCO solution was passed through the filter cartridgeinto the 100 L nitrogen-flushed reactor. The Pyrex bottle and thecartridge filter were rinsed with MeOH (7.5 L) and the solution wasadded to the reactor. The (4R,5R)-27 solution was added from the feedingvessel into the reactor at 37° C. over a period of 10 min, whilestirring. Methanol (6.5 L) was added to the Pyrex bottle and via thecartridge filter added to the feeding vessel to rinse the remaining(4R,5R)-27 into the reactor. The reaction mixture was brought to 50-60°C. over 10-20 min and stirred at that temperature for about 1 h. Themixture was cooled to 20-25° C. over a period of 1 h. To the reactionmixture, methyl t-butyl ether (MTBE) (42 L) was added over a period of 1h and stirred for a minimum of 1 h at 20-25° C. The suspension wasfiltered through a Büchner funnel. The reactor and the filter cake werewashed with MTBE (2×14 L). The solids were dried on a rotary evaporatorin a 20 L flask at 400-12 mbar, 40° C., for 22 h. A white crystallinesolid was obtained. The yield of 41 (Form I) was 3.08 kg (2.97 kg dry,93.8%) and the purity 99.7 area % (HPLC; Kromasil C4, 250×4.6 mm column;0.05% TFA in H₂O/0.05% TFA in ACN gradient. UV detection at 215 nm).

Example 12a Conversion of Form I of Compound 41 into Form II of Compound41

[0385] To 10.0 grams of Form I of 41 in a 400 mL jacketed reactor isadded 140 mL of MEK. The reactor is stirred (358 rpm) for 10 minutes at23° C. for 10 minutes and the stirring rate is then changed to 178 rpm.The suspension is heated to reflux over 1 hour using a programmedtemperature ramp (0.95° C./minute) using batch temperature control(cascade mode). The delta T_(max) is set to 5° C. The mixture is held atreflux for 1 hour. The mixture is cooled to 25° C. After 3 hours at 25°C., a sample of the mixture is collected by filtration. Filtration israpid (seconds) and the filtrate is clear and colorless. The white solidis dried in a vacuum oven (80° C., 25 in. Hg) to give a white solid. Theremainder of the suspension is stirred at 25° C. for 18 hours. Themixture is filtered and the cake starts to shrink as the mother liquorreaches the top of the cake. The filtration is stopped and the reactoris rinsed with 14 mL of MEK. The reactor stirrer speed is increased from100 to 300 rpm to rinse the reactor. The rinse is added to the filterand the solid is dried with a rapid air flow for 5 minutes. The solid isdried in a vacuum oven at 25 in. Hg for 84 hours to give Form II of 41.

EXAMPLE 13 Preparation of 2-(phenylthiomethyl)hexanal

[0386]

[0387] To a stirred mixture of n-butylacrolein (9.5 ml, 71.3 mmol) andEt₃N (0.5 mL, 3.6 mmol) at 0° C. under nitrogen is added thiophenol (7.3mL, 71.3 mmol) in 5 minutes. The mixture is allowed to warm to roomtemperature in 30 minutes. ¹H NMR of the reaction mixture sample willshow quantitative conversion. Et₃N is removed under reduced pressure.

EXAMPLE 14 Preparation of 2-((4-methoxyphenylthio)methyl)hexanal

[0388]

[0389] To a stirred mixture of n-butylacrolein (2.66 ml, 20 mmol) andEt₃N (0.14 mL, 1 mmol) at 0° C. under nitrogen is added4-methoxythiophenol (2.46 mL, 20 mmol) in 5 minutes. The mixture isallowed to warm to room temperature in 30 minutes. ¹HNMR of the reactionmixture sample will show quantitative conversion. Et₃N is then removedunder reduced pressure.

EXAMPLE 15 Preparation of 2-((4-chlorophenylthio)methyl)hexanal

[0390]

[0391] To a stirred mixture of n-butylacrolein (5.32 ml, 40 mmol) andEt₃N (0.28 mL, 2 mmol) at 0° C. under nitrogen is added4-chlorothiophenol (5.78 g, 40 mmol) in 5 minutes. The mixture isallowed to warm to room temperature in 30 minutes. ¹HNMR of the reactionmixture sample will show quantitative conversion. Et₃N is then removedunder reduced pressure.

EXAMPLE 16 Preparation of 2-(acetylthiomethyl)hexanal

[0392]

[0393] To a stirred mixture of n-butylacrolein (13.3 ml, 100 mmol) andEt₃N (0.7 mL, 5 mmol) at 0° C. under nitrogen is added thioacetic acid(7.2 mL, 100 mmol) in 5 minutes. The mixture is allowed to warm to roomtemperature in 30 minutes. ¹HNMR of the reaction mixture sample willshow quantitative conversion. Et₃N is then removed under reducedpressure.

EXAMPLE 17 Preparation of 2-methyl-3-phenylthiopropanal

[0394]

[0395] To a stirred mixture of 51.4 g (0.733 mole) of methacrolein and 2g (0.018 mole) of triethylamine at 0-5° C. is added 80.8 g (0.733 mole)of benzenethiol slowly. The addition rate is such that the temperaturewas under 10° C. The reaction mixture is stirred at 0-5° C. for onehour. The mixture is placed on a rotary evaporator to removetriethylamine.

EXAMPLE 18 Preparation of 2-(((4-chlorophenyl)sulfonyl)methyl)hexanal

[0396]

[0397] To a stirred solution of 4-chlorobenzosulfinate sodium salt (4.10g, 20.81 mmol) in 20 mL of acetic acid at 60° C. is added2-butylacrolein (3.8 mL, 28.56 mmol) slowly. The reaction mixture uskept at 50° C. for 3.5 hours. The mixture us diluted with 10 mL of waterand extracted with ethyl acetate (2×10 mL). The combined extract iswashed with saturated NaHCO₃, water, brine, and dried with MgSO₄. Afterremoving solvents, the product is obtained as a yellowish slightlyviscous oil in 94% yield.

EXAMPLE 19 Preparation of 2-(((4-methylphenyl)sulfonyl)methyl)hexanal

[0398]

[0399] To a stirred solution of 4-toluenesulfinate sodium salt (10.10 g,56.68 mmol) in 35 mL of acetic acid at 50° C. is added 2-butylacrolein(10.6 mL, 79.66 mmol) slowly. The reaction mixture is kept at 50° C. for3 hours. After cooling to room temperature, the mixture is diluted with50 mL of water and extracted with ethyl acetate (2×25 mL). The combinedextract is washed with saturated NaHCO₃, water, brine, and dried withMgSO₄. After removing solvents, the product is obtained as a yellowliquid in 75% yield.

EXAMPLE 20 Preparation of (4E)-2-(acetylthiomethyl)-2-butylhex-4-enal

[0400]

[0401] To a stirred solution of 2-(acetylthiomethyl)hexanal (32.6 g,0.173 mole) in 325 ml of xylenes in a 500-mL RBF fitted with aDean-Stark trap is added 2 hydroxy-3-butene (22.5 mL, 0.259 mole),followed by pyridinium p-toluenesulfonate (4.34 g, 0.017 mole) at roomtemperature under nitrogen. The mixture is heated to reflux overnight.After cooling to room temperature, the xylenes solution is washed with300 mL of saturated NaHCO₃ solution. The aqueous phase is extracted with300 mL of ethyl acetate. The combined organic extract is washed with 200mL of brine and 200 mL of water. After removing solvents, the product isobtained by vacuum distillation (157-160° C./1.5 mmHg) in 80.5% yield.

EXAMPLE 21 Preparation of (4E)-2-butyl-2-(phenylthiomethyl)hex-4-enal

[0402]

[0403] 2-(Phenylthiomethyl)hexanal (2.67 g, 12 mmol), 3-buten-2-ol (5mL, 58 mmol), and p-toluenesulfonic acid (0.05 g, 0.26 mmol) are addedto 25 ml of xylenes. The reaction mixture is heated to reflux using aDean-Stark trap to collect water. After 3 hours, the mixture is cooledto room temperature and diluted with ethyl acetate, which is washedsaturated NaHCO₃ solution, brine, and dried with MgSO₄. After removingsolvents, the crude product is purified by chromatography. The productis obtained in 78.6% as a colorless oil.

EXAMPLE 22 Preparation of (4E)-2-methyl-2-(phenylthiomethyl)-hept-4-enal

[0404]

[0405] 2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 1-penten-3-ol(21.67 g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole)are added to 90 ml of xylenes. The reaction mixture is heated to refluxusing a Dean-Stark trap to collect water. After 3 hours, the mixture iscooled to room temperature and quenched with 30 ml of saturated NaHCO₃solution. The two phases are separated and the aqueous phase isextracted with 30 ml of ethyl acetate. The combined organic extracts iswashed with 30 ml of brine and dried with Na₂SO₄. After removingsolvents, the crude product is purified by chromatography. The productis obtained in 77% as a colorless oil.

EXAMPLE 23 Preparation of (4E)-2-methyl-2-(phenylthiomethyl)-hex-4-enal

[0406]

[0407] 2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 3-buten-2-ol(18.04 g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole)are added to 90 ml of xylenes. The reaction mixture is heated to refluxusing a Dean-Stark trap to collect water. After 3 hours, the mixture iscooled to room temperature and quenched with 30 ml of saturated NaHCO₃solution. The two phases are separated and the aqueous phase isextracted with 30 ml of ethyl acetate. The combined organic extracts iswashed with 20 ml of brine and dried with Na₂SO₄. After removingsolvents, the crude product is purified by chromatography. The productis obtained in 74.3% as a colorless oil.

Example 24

[0408] Preparation of(4E)-2-butyl-2-(((4-chlorophenyl)sulfonyl)methyl)hex-4-enal

[0409] To a stirred solution of2-(((4-chlorophenyl)-sulfonyl)methyl)hexanal (3.38 g, 11.73 mmol) in 30ml of toluene in a RBF fitted with a Dean-Stark trap is added2-hydroxy-3-butene (5 mL, 57.73 mmol), followed by p-toluenesulfonicacid (0.13 g) at room temperature under nitrogen. The mixture is heatedto reflux for 20 hours. After cooling to room temperature, the toluenesolution is diluted with 10 mL of ethyl acetate and washed with 10 mL ofsaturated NaHCO₃ solution. The aqueous phase is extracted with ethylacetate. The combined organic extract is washed with water (2×10 mL),brine (1×10 mL), and dried with MgSO₄. After removing solvents, theproduct is obtained as a brownish oil in 98% yield.

EXAMPLE 25 Preparation of(4E)-2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hex-4-enal

[0410]

[0411] To a stirred solution of2-(((4-methylphenyl)-sulfonyl)methyl)hexanal (5.63 g, 21 mmol) in 35 mlof toluene in a RBF fitted with a Dean-Stark trap is added 2hydroxy-3-butene (10 mL, 115 mmol), followed by p-toluenesulfonic acid(0.13 g) at room temperature under nitrogen. The mixture is heated toreflux overnight. After cooling to room temperature, the toluenesolution is washed with saturated NaHCO₃ solution (2×10 mL), water (2×20mL), brine (1×20 mL), and dried with MgSO₄. After removing solvents, theproduct is obtained as a brownish oil in quantitative yield with a GCpurity of 89%.

EXAMPLE 26 Preparation of2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hexanal

[0412]

[0413] To a solution of 0.5 g of2-butyl-2-(((4-ethylphenyl)sulfonyl)methyl)hexanal in 30 mL of tolueneis added 5 mL of 37% formaldehyde and 220 mg of 20% Pd(OH)₂/C catalyst.The reaction mixture is purged with dry nitrogen gas (3×) and hydrogengas (3×) and hydrogenated at 60 psi H2 and 60° C. for 15 hours. Thecatalyst is removed by filtration and washed with ethanol (2×20 mL).Solvents of the combined washes and filtrate are removed under vacuum toyield the crude product.

[0414] For the following examples ¹H and ¹³C NMR spectra were recordedon a Varian 300 spectrometer at 300 and 75 MHz respectively. The ¹Hchemical shifts are reported in ppm downfield from tetramethylsilane.The ¹³C chemical shifts are reported in ppm relative to the center lineof CDCl₃ (77.0 ppm). Melting points were recorded on a Buchi 510 meltingpoint apparatus and are uncorrected. HPLC data was obtained on a SpectraPhysics 8800 Chromatograph using a Beckman Ultrasphere C18 250×4.6 mmcolumn. HPLC conditions: detector wavelength=254 nm, sample size=10 μL,flowrate=1.0 mL/min, mobile phase=(A) 0.1% aqueous trifluoroacetic acid:(B) acetonitrile. Quantitative HPLC analysis was determined by runningsamples of known concentration of the crude product and of purifiedproduct, adjusting the peak areas for concentration differences, anddividing the peak area of the crude sample by the peak area of thepurified sample. HPLC Gradient: Time % A % B  0 min 50 50  5 min 50 5030 min 0 100 40 min 0 100

EXAMPLE 27 Preparation of Compound 32

[0415]

[0416] Procedure A: Na₂S.9H₂O (8.64 g, 36.0 mmol) and sulfur (1.16 g,36.0 mmol) were combined in a 50 mL round-bottom flask. The mixture washeated to 50° C. until homogeneous, and water (10.0 mL) was added.Compound 33 (10.00 g, 36.0 mmol) and ethanol (100 mL) were combined in a500 mL round-bottom flask. The reaction flask was purged with N₂ andequipped with mechanical stirrer. The reaction mixture was heated to 65°C. until homogeneous, and then increased to 74° C. The disulfidesolution was added to the 500 mL reaction flask over 10 minutes. After1.5 hrs at reflux, analysis of an aliquot by HPLC indicated completeconversion of 33. Aqueous 18% NaOH (20.0 g, 90.0 mmol) was added over 5minutes (endothermic). After 15 minutes, the reaction mixture was cooledto 0° C., and 30% H₂O₂ (16.00 g, 140.0 mmol) was added dropwise keepingtemp below 20° C. After 1.5 hrs at <20° C., analysis of an aliquot byHPLC indicated total oxidation of the sodium thiophenolate intermediate.The ethanol was removed under reduced pressure at <65° C. Water (100 mL)was added, and the mixture was washed with CH₂Cl₂ (100 mL). 10% HCl (˜40mL) was added until pH=1, and the reaction mixture was extracted withCH₂Cl₂ (100.0 mL). 2-Butylacrolein (5.20 mL, 39.2 mmol) was added to theorganic extract, and the mixture was stirred for 1 hour. Analysis of analiquot by HPLC indicated very little sulfinic acid intermediate. Theorganic layer was concentrated in vacuo to give an amber solid (14.19g). Analysis by quantitative HPLC indicated 84% purity, whichcorresponds to 11.92 g Michael adduct (79% yield of 32 based on 33).

[0417] Procedure B: Compound 33 (4.994 g, 17.98 mmol) anddimethylacetamide (21.0 mL) were combined in a dry 250 mL round-bottomflask. The reaction flask was purged with N₂, equipped with magneticstirrer, and heated to 40° C. until the mixture became homogeneous.Na₂S.3H₂O (2.91 g, 22.37 mmol) and water (4.0 mL) were combined in aseparate flask and heated to 55° C. until homogeneous. The Na₂S solutionwas then added portion-wise to the reaction flask over 25 minutes. After2.5 hrs at 40° C., analysis of an aliquot by HPLC indicated completeconversion of 33. After 2 hrs more, the reaction mixture was cooled to30° C., and aq. 18% NaOH (10.02 g, 44.90 mmol) was added. After 20 min,the reaction mixture was cooled to 0° C., and 30% H₂O₂ (8.02 g, 70.6mmol) was added dropwise over 30 minutes while maintaining a temperatureof less than 15° C. After 10 min, an aliquot was removed and analyzed byHPLC, which indicated >93% oxidation of the sodium thiophenolateintermediate. After 1 hr, Na₂SO₃ (6.05 g, 48.0 mmol) and water (50.0 mL)were added, and the cooling bath was removed. After 20 min, the mixturewas washed with toluene (or CH₂Cl₂) (2×50.0 mL). Toluene (or CH₂Cl₂)(50.0 mL), 2-butylacrolein (2.60 mL, 19.6 mmol), and n-Bu₄NI (0.032 g,0.087 mmol) were added, and the reaction mixture was cooled to 0° C. Tothis, 10% HCl (˜30 mL) was added until pH=1. The cooling bath wasremoved, and the reaction mixture was stirred for 30 min. Analysis of analiquot of the aqueous layer by HPLC indicated very little sulfinic acidintermediate. After 30 min more, the aqueous layer was separated anddiscarded. The organic layer was kept at −10° C. overnight, stirred atR.T. for 5 hrs. Analysis of the toluene solution by quantitative HPLCindicated 6.444 g Michael adduct, (85% yield of 32 based on 3.

[0418] For characterization, a portion of the crude product wasconcentrated in vacuo and precipitated from ethyl ether to afford ayellow solid: mp 62.0-76.0° C.; HPLC (CH₃CN/H₂O): rt=22.4 min. ¹H NMR(CDCl₃) ????????t, J=6.0 Hz, 3H), 1.24 (m, 4H), 1.53 (m, 1H), 1.70 (m,1H), 2.83 (dd, J=14.1, 4.2 Hz, 1H), 2.98 (m, 1H), 3.56 (dd, J=14.4, 7.8Hz, 1H), 3.79 (s, 3H), 4.53 (s, 2H), 6.87 (dd, J=6.6, 2.4 Hz, 2H), 7.13(d, J=8.7 Hz, 2H), 8.12 (s, 1H), 8.20 (d, J=1.2 Hz, 2H), 9.53 (d, J=0.9Hz, 1H). ¹³C NMR (CDCl₃) ? 13.6, 22.4, 28.1, 28.5, 37.4, 45.4, 53.9,55.2, 114.4, 121.7, 127.3, 129.6, 130.3, 132.1, 142.7, 144.1, 150.7,158.7, 199.5. HRMS (ES+) calcd for C₂₁H₂₅NO₆S+NH₄: 437.1731, found:437.1746. Anal. (C₂₁H₂₅NO₆S): C, 60.13; H, 6.01; N, 3.34; O, 22.88; S,7.64. Found: C, 60.22; H, 5.98; N, 3.32; O, 22.77; S, 7.73.

EXAMPLE 28 Preparation of Compound 18a

[0419]

[0420] Procedure A: Compound 32 (11.577 g, 27.598 mmol),p-toluenesulfonic acid monohydrate (0.6115 g, 3.21 mmol), CH₂Cl₂ (70 ml)and 3-buten-2-ol (13.91 mL, 160.5 mmol) were combined in a dry 250 mLround-bottom flask. The reaction flask was purged with N₂ and equippedwith magnetic stirrer, Dean Stark trap, and reflux condenser. Thereaction mixture was heated to reflux. After 10.25 hrs, analysis of analiquot by HPLC indicated 78.6% 18a, 13.3% pre-Claisen enol ether, 3.7%32 and approximately 4% byproducts. K₂CO₃ (1.50 g, 10.8 mmol) was addedto the reaction flask. After 2.5 hrs, CH₂Cl₂ (50.0 mL) was added, andthe mixture was filtered through celite. The filtrate was collected andconcentrated in vacuo to yield an amber oil (15.73 g). Quantitative HPLCwas performed using a sample of purified 18a. The total peak area of thecrude product was determined by summing the pre-Claisen enol ether and18a peaks. It was assumed that they have the same HPLC response factors.Analysis by quantitative HPLC indicated 90% purity, which corresponds to14.20 g 18a and pre-Claisen enol ether 47, (94% yield of 18a based on32).

[0421] Procedure B: Compound 32 (5.43 g, 12.9 mmol), 3-buten-2-ol (76.16g, 85.4 mmol), p-toluenesulfonic acid monohydrate (0.258 g, 1.36 mmol)and toluene (51.0 mL) were combined in a 100 mL round-bottom flask. Thereaction flask was purged with N₂ and equipped with magnetic stirrer,Dean Stark trap, condenser, and vacuum line. The condenser was cooled to−10° C. via a Cryocool bath, and the Dean Stark trap was filled with3-buten-2-ol (about 111 mL). The reaction flask was evacuated to 107.5mmHg via a pressure controller and heated to 49° C. After 4 hrs, thereaction flask was cooled to R.T. and concentrated in vacuo at 30° C.The crude product was collected as an amber oil (8.154 g). QuantitativeHPLC was performed using a sample of purified 18a. The total peak areaof the crude product was determined by summing the pre-Claisen enolether and 18a peaks. It was assumed that they have the same HPLCresponse factors. Analysis by quantitative HPLC indicated 69% purity,which corresponds to 5.626g 18a and pre-Claisen enol ether 47, (80%yield of 18a based on 32)):

[0422] HPLC (CH₃CN/H₂O): 18a: rt=32.56, 32.99, 33.09 min, pre-Claisenenol ether: rt=30.7 min. ¹H NMR (CDCl₃) ? 0.84-0.93 (m, 3H), 1.09-1.34(m, 10H), 1.40-1.70 (m, 2H), 2.16-2.35 (m, 1H), 2.88-2.98 (m, 1H),3.52-3.63 (m, 1H), 3.80 (m, 3H), 3.84-4.10 (m, 2H), 4.49 (s, 1H), 4.50(s, 1H), 4.59 (d, J=3.0 Hz, 0.25H), 4.60 (d, J=2.7 Hz, 0.25H), 4.65 (d,J=2.4 Hz, 0.251H), 4.70 (d, J=2.4 Hz, 0.25H), 5.00-5.18 (m, 4H),5.42-5.84 (m, 2H), 6.87 (d, J=8.7 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H),7.12-7.17 (m, 2H), 8.02 (t, J=2.4 Hz, 1H), 8.14-8.17 (m, 1H), 8.23-8.27(m, 1H); ¹³C NMR (CDCl₃) ??13.8, 20.1, 20.9, 21.0, 21.4, 21.51, 21.57,21.6, 22.53, 22.55, 22.57, 28.7, 28.8, 28.94, 28.99, 29.0, 29.3, 29.4,29.8, 37.1, 37.2, 37.3, 38.73, 38.75, 53.3, 55.2, 55.60, 55.66, 55.7,55.9, 73.4, 73.5, 73.8, 73.9, 74.3, 75.1, 75.9,97.7,98.3,98.4,99.5,113.6, 114.4, 114.5, 114.9, 115.7, 115.9, 116.1, 116.3, 116.7, 116.9,121.22, 121.26, 121.31, 121.34, 126.70, 126.75, 126.8, 129.73, 129.77,130.45, 130.48, 130.5, 131.51, 131.51, 131.57, 139.6, 139.8, 139.9,140.1, 140.2, 140.3, 143.6, 143.70, 143.71, 143.81, 143.84, 144.26,144.29, 144.34, 144.35, 144.37, 150.5, 158.6; HRMS (ES+) calcd forC₂₉H₃₉NO₇S+NH₄: 563.2791, found: 563.2804.

EXAMPLE 29 Preparation of Compound 31

[0423]

[0424] Procedure A: A crude mixture of 18a and pre-Claisen enol ether 47(13.636 g, 24.989 mmol), o-xylene (75.0 mL), and calcium hydride (0.334g, 7.93 mmol) were combined in a dry 250 mL round-bottom flask. Thereaction flask was purged with N₂, equipped with magnetic stirrer, andheated to 145° C. After 3 hours, an aliquot was removed and analyzed byHPLC, which indicated 93% 31, 1% 32, 3% pre-Claisen enol ether 47, and4% byproducts. The reaction mixture was cooled to RT and filteredthrough celite washing with o-xylene (50.0 mL). The crude product wasconcentrated in vacuo and collected as an amber oil (11.525g). Analysisby quantitative HPLC indicated 86% purity, which corresponds to 9.9115gClaisen product (80% yield based on the mixture of 31 and pre-Claisenenol ether 47).

[0425] Procedure B: A crude mixture of 18a and pre-Claisen enol ether 47(2.700 g, 4.948 mmol), toluene (15.0 mL) and calcium hydride (0.0704g,1.67 mmol) were combined in a dry Fischer-Porter bottle. The reactionflask was purged with N₂, equipped with magnetic stirrer, and heated to145° C. After 10 hours, analysis of an aliquot by HPLC indicated 90.9%Claisen product 31), 2.8% pre-Claisen enol ether 47, 1.3% 18a and 5%byproducts. Toluene (30.0 mL) was then added, and the mixture wasfiltered through celite. Concentration in vacuo of the filtrate affordedthe crude product as an amber oil (2.6563 g). Analysis by quantitativeHPLC indicated 82% purity, which corresponds to 2.1782 g Claisen product31, (93% yield based on the mixture of 18a and pre-Claisen enol ether47).

[0426] Procedure C: Purified 18a (0.228 g, 0.417 mmol) was placed in a100 mL round-bottom flask. The reaction flask was placed in a Kugelrohrapparatus and evacuated to 100 mtorr. After 1 hr, the apparatus washeated to 40° C. After 15 minutes more, the apparatus was heated to 145°C. After 1 hr, the apparatus was cooled to R.T. to afford an dark oil(0.171 g). Analysis by HPLC indicated 88% Claisen product 31, 3%pre-Claisen enol ether 47 3% 18a and 6% byproducts. This corresponds toan 81% yield based on 18a. Quantitative HPLC was not performed.

[0427] For characterization, a portion of the residue was purified byflash column chromatography on silica gel (eluting with EtOAc/hexanes),concentrated in vacuo, and the desired product was collected as an amberoil: HPLC(CH₃CN/H₂O): rt=29.1 min. ¹H NMR (CDCl₃) ??0.88 (t, J=6.9 Hz,3H), 1.06 (m, 1H), 1.17-1.34 (m, 3H), 1.61 (d, J=6.3 Hz, 3H), 1.68 (m,1H), 1.83-1.93 (m, 1H), 2.42 (dd, J=14.4, 6.6 Hz, 1H), 2.63 (dd, J=14.7,8.1 Hz, 1H), 3.12 (s, 2H), 3.80 (s, 3H), 4.52 (ABq, 2H), 5.16-5.26 (m,1H), 5.52-5.64 (m, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H),8.09 (s, 1H), 8.21 (s, 1H), 8.22 (s, 1H), 9.40 (s, 1H)?? ¹³C NMR (CDCl₃)? 13.7, 17.9, 22.8, 25.6, 32.6, 35.9, 37.2,52.6, 55.1, 57.2, 114.4,121.7, 123.4, 127.1, 129.8, 130.2, 131.2, 131.5, 143.7, 144.5, 150.5,158.7, 202.5. HRMS (ES+) calcd for C₂₅H₃₁NO₆S+NH₄: 491.2216, found:491.2192. Anal. (C₂₅H₃₁NO₆S): C, 63.40; H, 6.60; N, 2.96; 0, 20.27; S,6.77. Found: C, 63.36; H, 6.39; N, 3.05; 0, 20.59; S, 6.71.

Other Reactions to Form Claisen Product 31

[0428] General procedure for other reactions of acetal to: In a typicalreaction, the purified acetal 18a is combined with solvent, base andwater removing agent (if indicated) and heated. The zeolites andmolecular sieves are activated at 300° C. The reported conversion isbased on the peak area of 31 vs. 18a in the HPLC data. The reportedyield is based on the peak area of the products vs. byproducts in theHPLC data. The results are summarized below. Ex- amp- le No.Base/Conditions Results 30 100° C. 95% conv./32% yield @ 4 hrs. 31 4 Asieves/o-xylene/145° C. 6% conv./39% yield @ 5 hrs. 32 o-xylene/120° C.100% conv./58% yield @ 2.5 33 o-xylene/145° C. 100% conv./70% yield @ 2hrs. 34 CH₃CN/140° C. 0% conv. @ 6 hrs. 35 PPTS(0.1 eq.)/pyr.(0.15eq.)/o- 84% conv./74% yield @ 3 hrs. xylene/120° C. 36 PPTS(0.13 eq.)/4A sieves/o- 21% conv./74% yield @ 1 hrs. xylene/120° C. 37 pyr.(9.0eq.)/CH₃CN/140° C. 0% conv. @ 2.5 hrs. 38 pyr.(12.3 eq.)/xylenes/140° C.1% conv./100% yield @ 2 hrs. 39 Et₃N(0.3 eq.)/o-xylene/145° C. 19%conv./78% yield @ 6 hrs. 40 CaH₂(0.46 eq.)/4 A sieves/o- 97% conv./92%yield @ 5 hrs. xylene/145° C. 41 CaH₂(0.3 eq.)/PhCH₃/145° C. 96%conv./95% yield @ 10 hrs. 42 CaH₂(0.43 eq.)/PTSA(0.07 eq.)/ 100%conv./34% yield @ 1 hrs. 4 A sieves/o-xylene/145° C. 43 CaH₂(0.42 eq.)/4A 0.2% conv./11% yield @ 8 hrs. sieves/CH₂Cl₂/145° C. 44 PhCH₃/prefilterthrough basic 98% conv./79% yield @ 3.5 hrs. alumina/145° C. 45AlCl₃(2.0 eq.)/Et₃N(4.1 0% conv. @ 4 hrs. eq.)/THF/25° C. 46Pd(PhCN)₂Cl₂ (0.1 eq.)/ reversion to 32. THF/25° C. 47 BF₃.OEt₂(1.2eq.)/ reversion to 32. CH₂Cl₂/−50° C. 48 HMDS/TMSI/CH₂Cl₂/25° C. 0%conv. @ 5 hrs.

Other Reactions to Form Acetal 18a and the Pre-Claisen Enol Ether 47

[0429] General procedure: In a typical reaction, the sulfone aldehyde 32is combined with 3-buten-2-ol (about 5 to about 50 eq.), solvent andacid source indicated. If indicated, 4 A molecular sieves (50 wt %), andtrimethyl orthoformate TMOF (1.2 eq.) are added to the reaction flask.If no solvent is indicated, 3-buten-2-ol is the solvent. The zeolitesand molecular sieves are activated at 300° C. The observed products area mixture of the acetal 18a and the pre-Claisen enol ether, asdetermined by LCMS and NMR. The reported conversion is based on the peakarea of product(s) vs. 32 in the HPLC data. The reported yield is basedon the peak area of the products vs. byproducts in the HPLC data. Theresults are summarized below. Example No. Acid/Conditions Results 49TFA(0.24 eq.)/CH₃CN/4 Å 2.5% conv./50% yield @ 18 hrs. sieves/25° C. 50TFA(3.5 eq.)/4 Å sieves/50° C. 42% conv./74% yield @ 4.5 hrs. 51 TFA(3.8eq.)/Isopropenyl acetate(3.3 44% conv./95% yield @ eq.)/50° C. 2 hrs. 52TFA(3.5 eq.)/65° C. 68% conv./86% yield @ 5.5 hrs. 53 TFA(3.0 eq.)/90°C. 73% conv./75% yield @ 5.5 hrs. 54 TFA(3.0 eq.)/PhCH₃/4 Å 90%conv./53% yield @ 58 hrs. sieves/TMOF/120° C. 55 TFA(3.0 eq.)/CH₃CN/4 Å92% conv./58% yield @ 41 hrs. sieves/TMOF/120° C. 56 PTSA(0.1 eq.)/25°C. 78% conv./100% yield @ 16 hrs. 57 PTSA(0.1 eq.)/4 Å sieves/50° C. 87%conv./99% yield @ 2 hrs. 58 PTSA(0.1 eq.)/4 Å sieves/70° C. 95%conv./92% yield @ 5.75 hrs. 59 PTSA(0.1 eq.)/4 Å sieves/90° C. 87%conv./74% yield @ 2 hrs. 60 PTSA(0.1 eq.)/Isopropenyl acetate (3.3 63%conv./94% yield @ 2.5 eq.)/50° C. hrs. 61 PTSA(0.12 eq.)/Isopropenylacetate 83% conv./91% yield @ (3.2 eq./90° C. 1 hrs. 62 PTSA(0.1eq.)/PhCH₃/4 Å 29% conv./70% yield @ 18 hrs. sieves/TMOF/90° C. 63PTSA(0.3 eq.)/PhCH₃/4 Å 37% conv./70% yield @ 70 hrs. sieves/TMOF/120°C. 64 PTSA(0.1 eq.)/PhCH₃/49° C. @ 95% conv./93% yield @ 3.5 hrs. 107.5mmHg 65 PTSA(0.1 eq.)/o-xylene/4 Å 92% conv./96% yield @ 3.5 hrs.sieves/50° C. 66 PTSA(0.1 eq.)/o-xylene/50° C. 59% conv./58% yield @ 7.5hrs. 67 PTSA(0.1 eq.)/CH₂Cl₂/4 Å 95% conv./100% yield @ 3.5 hrs.sieves/47° C. 68 PTSA(0.05 eq.)/CH₂Cl₂/4 Å 95% conv./99% yield @sieves/47° C. 5 hrs. 69 PTSA(0.025 eq.)/CH₂Cl₂/4 Å 15% conv./91% yield @6.5 hrs. sieves/47° C. 70 PTSA(0.1 eq.)/CH₂Cl₂/47° C. 100% conv./96%yield @ 1 hrs. 71 PTSA(0.1 eq.)/EtOAc/90° C. 75% conv./85% yield @ 5hrs. 72 PTSA(0.1 eq.)/EtOAc/4 Å sieves/50° C. 44% conv./85% yield @ 1.5hrs. 73 PTSA(0.1 eq.)/iPrOAc/4 Å sieves/50° C. 62% conv./93% yield @ 6hrs. 74 PTSA(0.1 eq.)/BuOAc/4 Å sieves/50° C. 72% conv./69% yield @ 6hrs. 75 PTSA(0.1 eq.)/THF/4 Å 63% conv./94% yield @ sieves/50° C. 7 hrs.76 PTSA(0.24 eq.)/CH₃CN/4 Å sieves/25° $$ 85% conv./100% yield @ 19 hrs.77 PTSA(0.1 eq.)/MIBK/4 Å sieves/50° C. 59% conv./95% yield @ 3 hrs. 78PTSA(0.1 eq.)/PhCF₃/50° C. 55% conv./65% yield @ 4 hrs. 79 PTSA(0.15eq.)/Pd(PhCN)₂Cl₂ 100% conv./97% yield @ (0.09 eq.)/4 Å sieves/25° C. 23hrs. 80 PPTS(0.1 eq.)/4 Å sieves/ 65% conv./87% yield @ 90° C. 7.5 hrs.81 CBV 5020 zeolites(25 wt %)/CH₃CN/25 30% conv./97% yield @ 22 hrs. 82CBV 5020 zeolites(25 wt %)/ 81% conv./99% yield @ 4 Å sieves/50° C. 2hrs. 83 CBV 5020 zeolites(25 wt %)/ 66% conv./94% yield @ 4 Å sieves/70°C. 24 hrs. 84 CBV 5020 zeolites(25 wt %)/ 81% conv./98% yield @ 4 Åsieves/90° C. 1 hrs. 85 CBV 5020 zeolites(25 wt %)/ 71% conv./93% yield@ 90° C. 2 hrs 86 CBV 5020 zeolites(25 wt %)/Isopropeny 79% conv./91%yield @ acetate 1.5 hrs. (3.0 eq.)/90° C. 87 CBV 5020 zeolites(10 wt%)/PhCH₃/4 Å 40% conv./53% yield @ sieves/TMOF/ 21 hrs. 120° C. 88300WN0030 g zeolites(10 wt %)/PhCH₃$$ 22% conv./57% yield @ sieves/ 21hrs. TMOF/120° C. 89 Montmorillonite K10(10wt. %)/PhCH₃/$$ 70% conv./64%yield @ sieves/TMOF/120° C. 57 hrs. 90 Montmorillonite K10(20wt %)/ 4%conv./99% yield @ 4 Å sieves/25° C. 18 hrs. 91 Montmorillonite K10(20wt%)/CH₃CN/$$ 4% conv./99% yield @ sieves/25° C. 21 hrs. 92 Amberlyst15(20wt. %)/ 49% conv./96% yield @ CH₂Cl₂/4 Å sieves/47° C. 2 hrs. 93Acetic acid(0.24 eq.)/ 0% conv./0% yield @ CH₃CN/4 Å sieves/25° C. 22hrs. 94 Acetic acid(3.0 eq.)/90° C. 15% conv./78% yield @ 2.5 hrs. 95Acetic acid (3.0 eq.)/4 Å sieves/90° C. 79% conv./84% yield @ 6.5 hrs.96 HCl (0.20 eq.)/25° C. 3% conv./6% yield @ 1 hrs. 97 HCl (4.1 eq.)/4 Åsieves/ 87% conv./98% yield @ 25° C. 2.5 hrs. 98 HCl (1.1 eq.)/dioxane/4Å sieves/25° C. 67% conv./100% yield @ 1 hrs. 99 HCl (1.1 eq.)/CH₂Cl₂/4Å sieves/47° C. 69% conv./100% yield @ 1 hrs. 100 AlClEt₂/(0.16 eq.)/4 Åsieves/25° C. 80% conv./59% yield @ 47 hrs. 101 Pd(PPh₃)₄ (0.10 eq.)/4 Åsieves/25° C. retro-Michael reaction only 102 Pd(PhCN)₂Cl₂ (0.10 eq.)/5% conv./47% yield @ THF/4 Å sieves/25° C. 4.5 hrs. 103 Pd(PhCN)₂Cl₂(0.12 eq.)/ 63% conv./100% yield @ 4 Å sieves/25° C. 2 hrs.

EXAMPLE 104 Preparation of Compound 29

[0430]

[0431] To a solution of 0.434 g of compound 31 in 30 mL of hot ethanolwas added 5 mL of 37% formaldehyde and 220 mg of 20% Pd(OH)₂/C catalyst.The reaction mixture was purged with nitrogen gas (3×) and H₂ (3×) andhydrogenated at 60 psi and 60° C. for 15 hours. The catalyst was removedby filtration and washed with ethanol (2×20 mL). Solvents of thecombined washes and filtrate were removed to yield 370 mg of crude 29(85%). An analytical sample was obtained by recrystallization fromethanol and water.

EXAMPLE 105 Preparation of Compound 12c

[0432]

[0433] A 1L 3-neck jacked flask is fitted with baffles, a bottom valve,an overhead stirred, an addition funnel, and a Neslab cooling bath. Tothe reactor is charged 35 grams of potassium thioacetate. The reactor isflushed with nitrogen gas and to it is charged 85 mL ofdimethylformamide (DMF). Mixing is started at 180 rpm and the bath iscooled to 18° C. The reactor is again flushed with nitrogen gas and toit is added 73.9 grams of compound 53 over 20 minutes via a droppingfunnel. The pot temperature is maintained at 23° C. during the addition.The mixture is stirred for 1 hour at about 23° C. to 27° C. To themixture is then added 80 mL of water followed by 100 mL of ethylacetate. The mixture is stirred for 20 minutes. The layers are allowedto separate and the aqueous layer is drained off. To the pot is addedanother 50 mL of water and the mixture is stirred for 15 minutes. Thelayers are separated and the aqueous layer is drained off. Then to thepot is added 50 mL of brine and the mixture is stirred for another 15minutes. The layers are separated and the aqueous layer is removed. Theorganic layer is concentrated under reduced pressure (water aspiratorpressure) at 47° C. to obtain 68.0 grams of orange oily compound 12c.

EXAMPLE 106 Preparation of Diethyl Acetal Compound 12d

[0434]

[0435] A 250 mL 3-neck round bottom flask is fitted with an overheadstirrer, a Teflon coated temperature probe, and a separatory funnel. Tothe flask is charged 78 g of compound 12c and 200 mL of ethanol. Thereactor is flushed with nitrogen gas and to it is charged 60 mL oftriethylorthoformate. Then to the flask is added 4 grams ofp-toluenesulfonic acid. The mixture is stirred at room temperature for16 hours. The mixture is then concentrated under reduced pressure and tothe flask is added 100 mL of ethyl acetate. Next is added 1.7 grams ofsodium bicarbonate in 50 mL of water. The mixture is stirred for 3minutes. The layers are allowed to separate and the aqueous layer isdrained. The organic layer is filtered through a pad of sodium sulfateand the organic layer is concentrated under reduced pressure (wateraspirator pressure) to afford 96.42 grams of orange oily compound 12d.

EXAMPLE 107 Preparation of Diethyl Acetal Compound 67

[0436]

[0437] A 0.5 L 3-neck jacked flask is fitted with baffles, a bottomvalve, an overhead stirrer, an addition funnel, a nitrogen inlet, asilicon oil bubbler, a Teflon-coated temperature probe, and aPolyScience cooling/heating bath. To the flask is charged 48.85 grams ofcompound 33. The flask is flushed with nitrogen gas and to it is charged75 mL of DMSO. The mixture is again flushed with nitrogen and agitationis begun. The jacket temperature is set at 40° C. and to the flask isadded 56.13 grams of compound 12d. Stirring is continued for 30 minutesand to the mixture is slowly added 28 mL of 50% aqueous NaOH over 120minutes via a dropping funnel. The mixture is stirred for 3 hours whilemaintaining the jacket temperature at 40° C. The reaction is allowed tocool to ambient temperature and the mixture is stirred for 15 hours(overnight). The jacket temperature is then adjusted to 5° C. and to themixture is slowly added 300 mL of water. The reaction is exothermic. Thebiphasic mixture is transferred to a separatory funnel and the mixtureis extracted with 2×150 mL of ethyl acetate. The layers were allowed toseparate for 30 minutes and the aqueous layer was drained off. The ethylacetate layers are combined. The combined ethyl acetate mixture isextracted successively with 400 mL and 100 mL of water. If the layers donot readily separate within 30 minutes, 50 mL of brine may be added tothe mixture to aid in separation of the layers. The aqueous layer isdrained off. The ethyl acetate layer is then extracted with 100 mL ofbrine. The ethyl acetate layer is then dried over anhydrous magnesiumsulfate and the solids are filtered off through a plug of activatedcharcoal/Supercel Hyflow. The filtrate is concentrated under reducedpressure and dried under vacuum for 18 hours to obtain 91.98 grams of anorange-brown, viscous oil (compound 67).

EXAMPLE 108 Conversion of Diethyl Acetal Compound 67 to1-(2,2-Dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene(29)

[0438]

[0439] Compound 67 (36 grams dissolved in 122 mL of ethyl acetate), 300mL acetic acid, 27.3 g of 37 wt % formaldehyde, and 50 mL of water arecharged into a 500 mL 1-neck round bottom flask in a Parr Shaker. To themixture is added 7.4 grams of 5% Pd/C (dry basis, Johnson Mathey). Thereactor is purged three times with nitrogen gas and then purged threetimes with hydrogen gas. The reactor is pressurized to 60 psi and heatedto 60° C. The temperature and pressure are held for 16 hours after whichtime the reactor is allowed to cool to room temperature. The reactionmixture is filtered through a pad of solka flock on a course frittedglass filter. The cake is washed twice with 40 mL of acetic acid andconcentrated to dryness under reduced pressure. The solid is mixed with100 mL ethanol and heated to 80° C. until all the solid is dissolved. Tothis is added 20 mL of tap water to form a homogeneous solution. Themixture is cooled to room temperature and to it is added 3 mL of ethylacetate. A white slurry forms. The slurry is heated to 60° C. until ahomogeneous solution forms. The mixture is cooled to room temperatureand held for two hours. During this time compound 29 crystallizes. Thesolids are filtered through a coarse fritted glass filter. The cake iswashed twice with 40 mL of a 20% (V/V) ethanol in water solution. Thecake is dried at 40-50° C. in a vacuum oven until no weight loss isobserved.

EXAMPLE 109 Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenalEthylene Glycol Acetal, 74

[0440]

[0441] Step 1. Preparation of 2-(Acetylthiomethyl)hexanal, 72.

[0442] A 1 L 3-neck round bottom flask is fitted with a magnetic stirbar, a nitrogen inlet, a thermometer probe connected to a temperaturemonitor, a 50 mL addition funnel, and an ice-water bath. Into the flaskis charged 37.0 ML of thiolacetic acid and the flask contents are cooledto 0-5° C. in the ice-water bath. To the flask is then charged 69.0 mLof butylacrolein via the addition funnel over 2 minutes. The temperatureincreases to a maximum of about 21° C. The reaction is cooled then toabout 10° C. and the flask is charged with 0.72 mL of triethylamine. Thetemperature increases to about 57° C. within about one minute. Stirringcontinues until the temperature drops to about 15° C. The resultingproduct mixture contains compound 72.

[0443] Step 2. Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenal,73.

[0444] The apparatus of Step 1 of this example is further fitted with aDean-Stark trap and a cold water condenser. The reaction flask,containing the product mixture of Step 1, is further charged with 50.0mL of 3-buten-2-ol, 1.987 g of p-toluenesulfonic acid monohydrate, and600 mL of toluene. The mixture is heated to about 105-110° C. withstirring for about 24 hours. During this time water, as well as some3-buten-2-ol and toluene collect in the Dean-Stark trap. The reaction iscomplete when no more water distills over. If desired, an additional 0.5equivalents of 3-buten-2-01 can be added to the flask to make up forloss from distillation. The mixture is allowed to cool to ambienttemperature. The resulting aldehyde mixture contains compound 73.

[0445] Step 3. Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenalEthylene Glycol Acetal, 74.

[0446] The apparatus and resulting aldehyde mixture of Step 2 of thisexample are further charged with 31.0 mL of ethylene glycol. The mixtureis heated with stirring to 105-110° C. for 2 hours. Water and toluenecollect in the Dean-Stark trap during this time. The reaction iscomplete when no more water distills over. The mixture is cooled toambient temperature and the reaction mixture is washed successively with100 mL of saturated sodium bicarbonate aqueous solution, 100 mL ofwater, and 100 mL of brine. The solvent is removed by evaporation in arotary evaporator. The yield is 149 grams of compound 74.

EXAMPLE 110 Preparation of Compound 67

[0447]

[0448] Step 1. Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenalDiethyl Acetal, 75.

[0449] A 250 mL 3-neck round bottom flask is fitted with an overheadstirrer, a Teflon coated temperature probe, and a separatory funnel. Tothe flask is charged 78 g of compound 74 and 200 mL of ethanol. Thereactor is flushed with nitrogen gas and to it is charged 60 mL oftriethylorthoformate. Then to the flask is added 4 grams ofp-toluenesulfonic acid. The mixture is stirred at room temperature for16 hours. The mixture is then concentrated under reduced pressure and tothe flask is added 100 mL of ethyl acetate. Next is added 1.7 grams ofsodium bicarbonate in 50 mL of water. The mixture is stirred for 3minutes. The layers are allowed to separate and the aqueous layer isdrained. The organic layer is filtered through a pad of sodium sulfateand the organic layer is concentrated under reduced pressure (wateraspirator pressure) to afford compound 75.

[0450] Step 2. Preparation of 2-butyl-2-(thiomethyl)hexanal DiethylAcetal, 76.

[0451] A 500 mL 3-neck round bottom flask is fitted with a condenser, amagnetic stir bar, a nitrogen inlet, a thermocouple connected to atemperature controller, and a heating mantle. The flask is purged withnitrogen gas and charged with 19.2 grams of compound 75, 96 mL ofN-methylpyrrolidone (NMP), 28.3 grams (2.5 equiv.) of p-toluenesulfonylhydrazide, and 18 mL (3.0 equiv.) of piperidine. While stirring, themixture is warmed to about 100° C. for 2 hours. The temperature is keptbelow 107° C. by removing the heat, if necessary. The mixture is cooledto ambient temperature. The product mixture contains compound 76. Ifdesired, this reaction can be run using 2.5 equiv. of p-toluenesulfonylhydrazide and 2.5 equiv. of piperidine.

[0452] Step 3. Preparation of Compound 67.

[0453] The equipment and product mixture of Step 2 of this example areused in this step. To the flask containing the product mixture of Step 2is charged 13.46 grams of compound 33 and 11.2 mL of 50% (w/w) aqueousNaOH. The mixture is heated to 100° C. with mixing and held at thattemperature for 2.5 hours. The mixture is cooled to ambient temperatureand to the flask is added 100 mL of ethyl acetate. This mixture iswashed with 100 mL of water. The aqueous layer is separated and washedwith 100 mL of ethyl acetate. The ethyl acetate layers are combined andwashed in succession with 3×100 mL of water and with 2×50 mL of brine.The organic layer is dried over magnesium sulfate and the solvent isremoved under vacuum in a rotary evaporator. The yield is 26 grams ofcompound 67 as a reddish brown oil.

EXAMPLE 111 Differential Scanning Calorimetry (DSC)

[0454] DSC experiments are performed either on a Perkin Elmer Pyris 7Differential Scanning Calorimeter or on a TA Instruments DifferentialScanning Calorimeter with 5-10 mg samples hermetically sealed in astandard aluminum pan (40 microliters) with a single hole punched in thelid. An empty pan of the same type is used as a reference. The heatingrate is 10° C./min with dry nitrogen purge. FIG. 9 shows typical DSCthermograms for Form I (plot(a)) and Form II (plot(b)) of compound 41.

EXAMPLE 112. X-Ray Powder Diffraction Patterns

[0455] X-ray powder diffraction experiments are conducted on an Ineltheta/theta diffraction system equipped with a 2 kW normal focus X-raytube (copper). X-ray scatter data are collected from 0 to 80° 2 theta.Samples are run in bulk configuration. Data are collected and analyzedon a Dell computer running Inel's software. In at least one case,samples are placed in a glass capillary tube and ends are sealed toprevent loss of solvent. The capillary is mounted on a special adapterin the path of the X-ray beam and data were collected.

[0456] Alternatively, the X-ray diffraction experiments are conducted ona system comprising a Siemens D5000 diffraction system equipped with a 2kW normal focus X-ray tube (copper). The system is equipped with anautosampler system with a theta-theta sample orientation. Datacollection and analysis is performed on a MS-Windows computer withSiemens' proprietary software.

[0457]FIG. 6 shows typical X-ray powder diffraction patterns for Form I(plot (a)) and Form II (plot(b)) of compound 41. Table 1 shows a summarycomparison of prominent X-ray powder diffraction peaks for Form I andForm II. TABLE 1 Form I Form II 2-Theta Relative Peak 2-Theta RelativePeak Value Intensity (%) Value Intensity (%) 7.203 15.0665 9.196218.6166 8.45 29.0688 12.277 29.2318 9.726 37.1457 12.584 8.39048 11.20549.0207 12.833 7.67902 11.786 10.8439 13.872 100 12.51 15.9267 14.28677.5682 13.342 11.0306 15.168 7.54978 14.25 16.3005 15.641 16.019414.859 16.1351 15.935 11.4935 15.526 43.0987 16.138 16.6656 15.87425.424 16.399 36.1255 16.309 14.278 16.544 77.6935 17.121 14.1898 17.09413.1102 17.498 13.173 17.645 38.4531 18.542 99.3626 18.511 33.022619.354 85.1982 18.826 91.0787 19.789 16.7251 19.128 25.2644 20.3439.3083 19.327 18.8639 20.891 27.5965 19.906 38.7122 21.297 16.226620.085 12.7865 22.022 26.6845 20.23 10.2004 23.304 42.0171 21.00 8.5843325.125 17.2159 21.48 47.6981 25.734 18.2944 21.729 33.6048 27.50325.8376 22.089 12.1403 32.056 12.7407 22.4 10.0712 35.188 22.4211 22.74813.3041 40.166 16.7913 22.959 14.5971 23.22 13.498 23.472 17.8224 23.96516.9247 24.553 16.8594 25.038 9.6835 25.299 13.0904 25.626 13.950325.767 14.9202 25.887 11.2996 26.343 18.1531 26.873 9.87736 27.94115.1787 28.228 15.4437 28.815 11.2996 29.475 13.7532 34.758 21.77340.176 21.0731

Example 113 Fourier Transform Infrared Spectra

[0458] The Fourier transform infrared (FTIR) spectra for Form I and FormII of compound 41 are obtained using a Bio-Rad FTS-45 Fourier-transforminfrared spectrometer equipped with a micro-ATR (attenuated totalreflectance) beam condensing accessory (IBM Corporation) mounted in thesample compartment of the instrument. The sample compartment and opticalbench of the spectrometer is under a nitrogen purge. The software usedfor operating the instrument and collecting the spectrum is Bio-Rad'sWindows 98-based Win-IR software. The spectra are obtained using an8-wavenumber resolution and 16 scans.

[0459] A small amount of sample is placed onto one side of a 5×10×1 mmKRS5 (a type of infrared transmitting material commonly used in the IRworld) ATR crystal, and lightly tamped with a stainless steel microspatula in order to ensure good contact of the sample with the face ofthe crystal. The crystal is mounted into the ATR beam-condensingaccessory, and the sample compartment allowed to purge for a few minutesto remove water vapor and carbon dioxide (their presence reduces thequality of the spectrum). This can be monitored on the screen of theoperating console, and when down to an acceptable level, the 16 scansare collected to produce an interferogram. Prior to analyzing thesample, a clean KRS5 crystal is mounted in the ATR accessory and abackground interferogram collected. The purge time and number of scansfor collecting the background should be the same as will be used foranalyzing the sample.

[0460] The Fourier-transform of the resulting interferogram isautomatically done and the spectrum appears on the screen. The resultingspectrum is then smoothed and baseline corrected, if necessary, then ATRcorrected to obtain a spectrum that is comparable to an absorption ortransmission spectrum.

[0461]FIG. 7 shows typical FTIR spectra for Form I (plot (a)) and FormII (plot (b)) of compound 41. Table 2 shows a summary comparison ofprominent FTIR peaks for Form I and Form II. TABLE 2 Form I Peaks FormII Peaks (cm⁻¹) (cm⁻¹) 3163 3250 2870 2885 1596 1600 1300 1288 1239 12251182 1172 1055 1050 986 990 855 858 825 837 627 620

Example 114 Solid-State Carbon-13 NMR Analysis

[0462] Solid-state NMR. Cross-polarization magic-angle spinning (CPMAS)¹³C NMR spectra were collected on a Monsanto-built spectrometeroperating at a proton resonance frequency of 127.0 MHz. Samples werespun at the magic angle with respect to the magnetic field in adouble-bearing rotor system at a rate of 3 kHz. CPMAS ¹³C NMR spectrawere obtained at 31.9 MHz following 2-ms matched, 50-kHz ¹H-¹³Ccross-polarization contacts. High-power proton dipolar decoupling(H₁(H)=65-75 kHz) was used during data acquisition. Residual spinningsidebands were suppressed using the Total Suppression of Sidebands(TOSS) method. In each experiment, approximately 219 mg of Form I andapproximately 142 mg Form II are used.

[0463]FIG. 8 shows typical solid-state ¹³C nuclear magnetic resonance(NMR) spectra for Form I (plot (a)) and Form II (plot (b)) of compound41. Table 3 shows a summary comparison of prominent solid-state ¹³C NMRpeaks for Form I and Form II. TABLE 3 Form I (ppm) Form II (ppm) 158.55157.971 151.712 142.325 145.986 137.172 140.852 134.043 136.628 127.232133.489 125.390 128.151 118.212 120.052 113.057 115.266 106.615 113.24176.795 109.928 68.512 76.795 57.100 68.860 47.712 54.523 43.661 46.23937.951 43.847 21.942 40.901 14.763 24.519 13.281 14.395 3.351

EXAMPLE 115 Water Uptake Experiments

[0464] Water sorption experiments are performed on a Dynamic VaporSorption (DVS) apparatus (DVS-1000 manufactured by Surface MeasurementsSystems, Inc.). Experiments are performed at 25° C. by initially dryingthe material of interest (about 10 mg sample) from 30% relative humidity(RH) (ambient room condition) to about 9% RH in a stepwise fashion (10%RH step) by purging with dry nitrogen until no further weight change wasobserved. The samples are then exposed to a stepwise (10% RH steps)increase in RH from about 0 to about 90% RH. Each successive step isinitiated when the change in weight over time at the relative humiditywas less than 0.0003% ((dm/dt)/m₀×100, where m is mass in mg, m₀ isinitial mass, and t is time in minutes). The sample is then takenthrough the reverse of the stepwise % RH increase. The data arecollected on a computer and analyzed using SMS' proprietary MS-Excelmacro interface software. FIG. 10 shows typical water sorption isothermresults for Form I (plot (a)) and Form II (plot (b)) of compound 41.Table 4 shows a summary comparison of water sorption and desorptionisotherms for Form I and Form II at 25° C. TABLE 4 Desorption Sorption %% Weight % RH at 25° C. Weight Change Change Form I 0.45 0.057 0.057 9.20.9575 0.997 20.05 2.016 2.1025 29.75 3.4105 3.599 39.4 4.282 4.74349.55 4.928 5.321 59.4 5.356 5.726 69.05 5.706 6.054 78.8 6.109 6.35788.5 6.734 6.734 Form II 1.3 −0.02695 −0.02695 9.35 0.04715 0.0423520.25 0.10585 0.09715 29.75 0.13755 0.14435 39.55 0.1809 0.1866 49.70.2386 0.2636 59.5 0.304 0.331 69.1 0.3945 0.3983 78.65 0.4695 0.484988.5 0.6446 0.6446

[0465] The examples herein can be performed by substituting thegenerically or specifically described reactants and/or operatingconditions of this invention for those used in the preceding examples.

[0466] The invention being thus described, it is apparent that the samecan be varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications and equivalents as would be obvious to one skilled inthe art are intended to be included within the scope of the followingclaims.

What is claimed is:
 1. A method for the preparation of a benzylammoniumcompound having the structure of Formula 60

wherein the method comprises treating a benzyl alcohol ether compoundhaving the structure of Formula (61)

under derivatization conditions to form a derivatized benzyl ethercompound having the structure of Formula (62)

and contacting the derivatized benzyl ether compound with an aminehaving the structure of Formula (2)

under amination conditions thereby producing the benzylammonium compoundor a derivative thereof, wherein: R¹ and R² independently are C₁ toabout C₂₀ hydrocarbyl; R³, R⁴, and R⁵ independently are selected fromthe group consisting of H and C₁ to about C₂₀ hydrocarbyl, whereinoptionally one or more carbon atom of the hydrocarbyl is replaced by O,N, or S, and wherein optionally two or more of R³, R⁴, and R⁵ takentogether with the atom to which they are attached form a cyclicstructure; R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CON³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM; R²³ and R²⁴ areindependently selected from the substituents constituting R³ and M; n isa number from 0 to 4; A⁻ is a pharmaceutically acceptable anion and M isa pharmaceutically acceptable cation; and X is a nucleophilicsubstitution leaving group.
 2. A method for the preparation of abenzylammonium compound having the structure of Formula (1)

wherein the method comprises treating a benzyl alcohol ether compoundhaving the structure of Formula (6)

under derivatization conditions to form a derivatized benzyl ethercompound having the structure of Formula (2)

and contacting the derivatized benzyl ether compound with an aminehaving the structure of Formula (42):

under amination conditions thereby producing the benzylammonium compoundor a derivative thereof, wherein: R¹ and R² independently are C₁ toabout C₂₀ hydrocarbyl; R³, R⁴, and R⁵ independently are selected fromthe group consisting of H and C₁ to about C₂₀ hydrocarbyl, whereinoptionally one or more carbon atom of the hydrocarbyl is replaced by O,N, or S, and wherein optionally two or more of R³, R⁴, and R⁵ takentogether with the atom to which they are attached form a cyclicstructure; and X is a nucleophilic substitution leaving group.
 3. Themethod of claim 2 wherein R³, R⁴, and R⁵ independently are selected fromthe group consisting of H and C₁ to about C₂₀ hydrocarbyl.
 4. The methodof claim 3 wherein R³, R⁴, and R⁵ independently are selected from thegroup consisting of H and C₁ to about C₁₀hydrocarbyl.
 5. The method ofclaim 4 wherein R³, R⁴, and R⁵ independently are C₁ to about C₁₀hydrocarbyl.
 6. The method of claim 5 wherein R³, R⁴, and R⁵independently are C₁ to about C₅ hydrocarbyl.
 7. The method of claim 6wherein R³, R⁴, and R⁵ independently are selected from the groupconsisting of methyl, ethyl, and propyl.
 8. The method of claim 7wherein R³, R⁴, and R⁵ each are methyl.
 9. The method of claim 2 whereinthe amine comprises a heterocycle.
 10. The method of claim 9 wherein theamine comprises a bicyclic heterocycle.
 11. The method of claim 10wherein the amine is 1,4-diazabicyclo[2.2.2]octane and thebenzylammonium compound has the structure of Formula (3)


12. The method of claim 2 wherein R¹ and R² independently are C₁ toabout C₁₀ hydrocarbyl.
 13. The method of claim 2 wherein R¹ and R²independently are C₁ to about C₅ hydrocarbyl.
 14. The method of claim 13wherein R¹ and R² are both butyl.
 15. The method of claim 14 wherein thebenzylammonium compound is an essentially racemic mixture ofenantiomers.
 16. The method of claim 14 wherein the benzylammoniumcompound produced by the method comprises a (4R,5R) enantiomer thatpreponderates over a (4S,5S) enantiomer.
 17. The method of claim 9wherein one of R¹ and R² is ethyl and the other of R¹ and R² is butyl.18. The method of claim 17 wherein the benzylammonium compound producedcomprises a (3R) enantiomer that preponderates over a (3S) enantiomer.19. The method of claim 17 wherein the benzylammonium compound producedcomprises a (3S) enantiomer that preponderates over a (3R) enantiomer.20. The method of claim 9 wherein the amination conditions comprise asolvent.
 21. The method of claim 20 wherein the solvent comprises ahydrophilic solvent.
 22. The method of claim 21 wherein the hydrophilicsolvent comprises a compound selected from the group consisting ofwater, a nitrile, an ether, an alcohol, a ketone, and an ester.
 23. Themethod of claim 22 wherein the hydrophilic solvent comprises a ketone.24. The method of claim 23 wherein the hydrophilic solvent comprises acompound selected from the group consisting of acetone and methyl ethylketone.
 25. The method of claim 24 wherein the hydrophilic solventcomprises methyl ethyl ketone.
 26. The method of claim 22 wherein thehydrophilic solvent comprises methyl ethyl ketone and water.
 27. Themethod of claim 21 wherein the solvent further comprises a hydrophobicsolvent.
 28. The method of claim 27 wherein the hydrophobic solvent isselected from the group consisting of an aliphatic hydrocarbon, anaromatic solvent, and a chlorinated solvent.
 29. The method of claim 27wherein the hydrophobic solvent comprises an aromatic solvent.
 30. Themethod of claim 29 wherein the hydrophobic solvent is selected from thegroup consisting of benzene, toluene, ethylbenzene, o-xylene, m-xylene,p-xylene, mesitylene, and naphthalene.
 31. The method of claim 30wherein the hydrophobic solvent is toluene.
 32. The method of claim 27wherein the solvent comprises methyl ethyl ketone, toluene, and water.33. The method of claim 20 wherein the solvent comprises a hydrophobicsolvent.
 34. The method of claim 9 wherein the amination conditionscomprise performing the amination at a temperature in the range of about0° C. to about 100° C.
 35. The method of claim 34 wherein the aminationconditions comprise performing the amination at a temperature in therange of about 15° C. to about 75° C.
 36. The method of claim 35 whereinthe amination conditions comprise performing the anination at atemperature in the range of about 20° C. to about 65° C.
 37. The methodof claim 2 further comprising an enantiomeric enrichment step.
 38. Themethod of claim 37 wherein the enantiomeric enrichment step compriseschiral chromatography.
 39. The method of claim 37 wherein theenantiomeric enrichment step comprises an asymmetric synthesis step. 40.The method of claim 37 wherein the enantiomeric enrichment stepcomprises crystallization of a diastereomeric salt.
 41. The method ofclaim 2 wherein X is selected from the group consisting of chloro,bromo, iodo, methanesulfonato, toluenesulfonato, benzenesulfonato, andtrifluoromethanesulfonato.
 42. The method of claim 41 wherein X isselected from the group consisting of chloro, bromo, and iodo.
 43. Themethod of claim 42 wherein X is chloro.
 44. The method of claim 2wherein the benzyl alcohol ether compound has an absolute configurationpredominantly of (4R,5R).
 45. The method of claim 2 wherein the benzylalcohol ether compound has an absolute configuration predominantly of(4S,5S).
 46. The method of claim 2 wherein the derivatization conditionscomprise contacting the benzyl alcohol ether compound with ahalogenating agent.
 47. The method of claim 46 wherein the halogenatingagent is selected from the group consisting of a thionyl halide, asulfuryl halide, a phosphorus trihalide, a phosphorus pentahalide, anoxalyl halide, and a hydrogen halide.
 48. The method of claim 47 whereinthe halogenating agent is a chlorinating agent.
 49. The method of claim47 wherein the halogenating agent is selected from the group consistingof thionyl chloride, phosphorus trichloride, phosphorus pentachloride,and hydrogen chloride.
 50. The method of claim 49 wherein thehalogenating agent is selected from the group consisting of thionylchloride, phosphorus trichloride, and phosphorus pentachloride.
 51. Themethod of claim 49 wherein the halogenating agent is thionyl chloride.52. The method of claim 47 wherein the halogenating agent comprises amixture of triphenylphosphine and a carbon tetrahalide.
 53. The methodof claim 47 wherein the halogenating agent comprises a mixture oftriphenylphosphine and carbon tetrachloride.
 54. The method of claim 2further comprising a step in which a benzyl alcohol ether compoundhaving the structure of Formula (6)

is prepared wherein the step comprises contacting a phenol compoundhaving the structure of Formula (4)

with a substituted xylene compound having the structure of Formula (5)

under substitution conditions to produce the benzyl alcohol ethercompound (6) wherein X² is a leaving group.
 55. The method of claim 54wherein the phenol compound has an absolute configuration of (4R,5R).56. The method of claim 54 wherein the phenol compound has an absoluteconfiguration of (4S,5S).
 57. The method of claim 54 wherein X² isselected from the group consisting of halo, methanesulfonato,toluenesulfonato, benzenesulfonato, and trifluoromethanesulfonato. 58.The method of claim 57 wherein X² is selected from the group consistingof chloro, bromo, and iodo.
 59. The method of claim 58 wherein X² ischloro.
 60. The method of claim 54 wherein R¹ and R² independently areC₁ to about C₁₀ hydrocarbyl.
 61. The method of claim 60 wherein R¹ andR² independently are C₁ to about C₅ hydrocarbyl.
 62. The method of claim61 wherein R¹ and R² are both butyl.
 63. The method of claim 61 whereinone of R¹ and R² is ethyl and the other of R¹ and R² is butyl.
 64. Themethod of claim 54 wherein the contacting of the phenol compound withthe substituted xylene compound is performed in the presence of asolvent.
 65. The method of claim 64 wherein the solvent comprises anamide.
 66. The method of claim 65 wherein the amide is selected from thegroup consisting of dimethylformamide and N,N-dimethylacetamide.
 67. Themethod of claim 54 wherein the contacting of the phenol compound withthe substituted xylene compound is performed in the presence of a base.68. The method of claim 67 wherein the base comprises a compoundselected from the group consisting of a metal hydroxide, a metalalcoholate, a metal hydride, an alkyl metal complex, and an amide base.69. The method of claim 68 wherein the base comprises a metal hydroxide.70. The method of claim 2 further comprising a deprotecting step whereina protected phenol compound having the structure of Formula (7)

is deprotected to form a phenol compound having the structure of Formula(4)

wherein R⁶ is a protecting group.
 71. The method of claim 70 wherein R⁶is a C₁ to about C₁₀ hydrocarbyl group.
 72. The method of claim 71wherein R⁶ is a C₁ to about C₁₀ alkyl group.
 73. The method of claim 72wherein R⁶ is a C₁ to about C₅ alkyl group.
 74. The method of claim 73wherein R⁶ is methyl.
 75. The method of claim 71 wherein thedeprotecting step comprises treating the protected phenol compound witha deprotection reagent.
 76. The method of claim 75 wherein thedeprotecting step comprises treating the protected phenol compound witha deprotecting reagent comprising a compound selected from the groupconsisting of a boron trihalide, a hydrogen halide, and a metalhydrocarbyl thiolate.
 77. The method of claim 76 wherein thedeprotecting reagent is selected from the group consisting of borontribromide, boron trichloride, hydrogen iodide, hydrogen bromide, andhydrogen chloride.
 78. The method of claim 77 wherein the deprotectingreagent is selected from the group consisting of boron tribromide andboron trichloride.
 79. The method of claim 77 wherein the deprotectingreagent is boron tribromide.
 80. The method of claim 77 wherein thedeprotecting reagent is a metal hydrocarbyl thiolate.
 81. The method ofclaim 80 wherein the deprotecting reagent is a lithium hydrocarbylthiolate.
 82. The method of claim 81 wherein the deprotecting reagent isa lithium C₁ to about C₁₀ alkyl thiolate.
 83. The method of claim 82wherein the deprotecting reagent is lithium ethanethiolate.
 84. Themethod of claim 75 wherein the deprotecting reagent comprises a sulfonicacid in combination with methionine.
 85. The method of claim 84 whereinthe deprotecting reagent comprises methanesulfonic acid in combinationwith methionine.
 86. The method of claim 85 wherein the deprotectingstep is performed substantially neat.
 87. The method of claim 85 whereinthe deprotecting step is performed in the presence of a solvent.
 88. Themethod of claim 87 wherein the solvent comprises a compound selectedfrom the group consisting of an alkane, an aromatic solvent, achlorinated solvent, a sulfonic acid, and an inorganic solvent.
 89. Themethod of claim 70 wherein the protected phenol compound has an absoluteconfiguration of (4R,5R).
 90. The method of claim 70 wherein theprotected phenol compound has an absolute configuration of (4S,5S). 91.The method of claim 2 further comprising a cyclization step wherein anamino sulfur oxide aldehyde compound having the structure of Formula

is treated under cyclization conditions to form a protected phenolcompound having the structure of Formula (7a)

wherein R⁶ is a protecting group, and y is 1 or
 2. 92. The method ofclaim 91 wherein R⁶ is a C₁ to about C₁₀ hydrocarbyl group.
 93. Themethod of claim 92 wherein R⁶ is a C₁ to about C₁₀ alkyl group.
 94. Themethod of claim 93 wherein R⁶ is a C₁ to about C₅ alkyl group.
 95. Themethod of claim 94 wherein R⁶ is methyl.
 96. The method of claim 91wherein the cyclization conditions comprise treating the amino sulfuroxide aldehyde with a base.
 97. The method of claim 96 wherein the basecomprises a compound selected from the group consisting of MOR¹¹, ametal hydroxide, and an alkyl metal complex, wherein R¹¹ is a C₁ toabout C₁₀ hydrocarbyl group and M is an alkali metal.
 98. The method ofclaim 97 wherein the base comprises MOR¹¹.
 99. The method of claim 98wherein M is selected from the group consisting of sodium, lithium, andpotassium.
 100. The method of claim 98 wherein R¹¹ is a C₁ to about C₁₀alkyl group.
 101. The method of claim 100 wherein R¹¹ is a C₁ to aboutC5 alkyl group.
 102. The method of claim 101 wherein R¹¹ is selectedfrom the group consisting of methyl, ethyl, isopropyl, and tert-butyl.103. The method of claim 102 wherein R¹¹ is tert-butyl.
 104. The methodof claim 103 wherein the base is potassium t-butoxide.
 105. The methodof claim 91 wherein the cyclization conditions comprise a solvent. 106.The method of claim 105 wherein the solvent comprises a hydrophilicsolvent.
 107. The method of claim 106 wherein the solvent is selectedfrom the group consisting of an ether and an alcohol.
 108. The method ofclaim 106 wherein the solvent is an ether.
 109. The method of claim 108wherein the solvent is selected from the group consisting oftetrahydrofuran, tetrahydrofuran, diethyl ether, methyl t-butyl ether,1,4-dioxane, glyme, and diglyme.
 110. The method of claim 109 whereinthe solvent is tetrahydrofuran.
 111. The method of claim 107 wherein thesolvent is an alcohol.
 112. The method of claim 111 wherein the solventis selected from the group consisting of methanol, ethanol, propanol,isopropyl alcohol, butanol, sec-butyl alcohol, isobutyl alcohol, andt-butyl alcohol.
 113. The method of claim 91 wherein y is
 1. 114. Themethod of claim 113 further comprising an oxidation step in which theamino sulfur oxide aldehyde compound is treated under oxidationconditions to form an amino sulfone aldehyde compound having thestructure of Formula (8)


115. The method of claim 91 wherein y is
 2. 116. The method of claim 2further comprising an reductive alkylation step in which a nitro sulfuroxide aldehyde compound having the structure of Formula (9a)

is reductively alkylated to form an amino sulfur oxide aldehyde compoundhaving the structure of Formula (8a)

wherein R⁶ is a protecting group, and z is 0, 1, or
 2. 117. The methodof claim 116 wherein z is 0 or
 1. 118. The method of claim 117 furthercomprising an oxidation step in which the nitro sulfur oxide aldehydecompound is treated under oxidation conditions to form a nitro sulfonealdehyde compound having the structure of Formula (9)


119. The method of claim 116 wherein z is
 2. 120. The method of claim 2further comprising a step for the preparation of an aniline sulfur oxidecompound having the structure of Formula (39)

wherein the step comprises reducing a nitro sulfur oxide aldehydecompound having the structure of Formula (9a)

to form the aniline sulfur oxide compound, wherein R⁶ is a protectinggroup, and z is 0, 1, or
 2. 121. The method of claim 120 furthercomprising a methylation step in which the aniline sulfur oxide compoundis treated under methylation conditions to form an amino sulfur oxidealdehyde compound having the structure of Formula (8a)


122. The method of claim 2 further comprising an oxidation step in whicha nitro sulfide aldehyde compound having the structure of Formula (10)

is oxidized to form a nitro sulfone aldehyde compound having thestructure of Formula (9a)

wherein R⁶ is a protecting group and z is 1 or
 2. 123. The method ofclaim 122 wherein z is
 2. 124. The method of claim 123 wherein z is 1.125. The method of claim 124 in which the oxidation conditions compriseenantioselective oxidation conditions.
 126. The method of claim 2further comprising a sulfide-forming step in which a substituteddiphenyl methane compound having the structure of Formula (11)

is coupled with a substituted propionaldehyde compound having thestructure of Formula (12)

in the presence of a source of sulfur to form a nitro sulfide aldehydehaving the structure of Formula (10)

wherein R⁶ is a protecting group; X³ is an aromatic substitution leavinggroup; and X⁴ is a nucleophilic substitution leaving group.
 127. Themethod of claim 2 further comprising a reduction step in which asubstituted benzophenone compound having the structure of Formula (13)

is reduced to form a substituted diphenyl methane compound having thestructure of Formula (11)

wherein R⁶ is a protecting group and X³ is an aromatic substitutionleaving group.
 128. The method of claim 2 further comprising anacylation step in which a protected phenol compound having the structureof Formula (14)

is treated with a substituted benzoyl compound having the structure ofFormula (15)

under acylation conditions to produce a substituted benzophenonecompound having the structure of Formula (13)

wherein R⁶ is a protecting group, X³ is an aromatic substitution leavinggroup, and X⁵ is selected from the group consisting of hydroxy and halo.129. The method of claim 2 further comprising one or more steps in whichan amino sulfone aldehyde compound having the structure of Formula (17)

is prepared wherein an alkenyl sulfone aldehyde compound having thestructure of Formula (16)

is reduced and reductively alkylated to form the amino sulfone aldehydecompound (17), wherein R¹ is a C₁ to about C₂₀ hydrocarbyl group, R⁶ isa protecting group, and R¹² is a C₁ to about C₁₀ hydrocarbyl group. 130.The method of claim 2 further comprising a thermolysis step wherein anacetal compound having the structure of Formula (18)

is thermolyzed to form an alkenyl sulfone aldehyde compound having thestructure of Formula (16)

wherein R¹ is a C₁ to about C₂₀ hydrocarbyl group; R⁶ is a protectinggroup; R⁷ is selected from the group consisting of H and C₁ to about C₁₇hydrocarbyl; and R¹³ is selected from the group consisting of H and C₁to about C₂₀ hydrocarbyl.
 131. The method of claim 130 in which R¹³ is agroup having the structure of Formula (43)


132. The method of claim 2 further comprising an acetal-forming step inwhich a monoalkyl sulfone aldehyde compound having the structure ofFormula (19)

is reacted with an allyl alcohol compound having the structure ofFormula (20)

optionally in the presence of a hydroxylated solvent having thestructure HOR¹³ to form an acetal compound having the structure ofFormula (18)

wherein: R¹ is a C₁ to about C₂₀ hydrocarbyl; R⁶ is a protecting group;R⁷ is selected from the group consisting of H and a C₁ to about C₁₇hydrocarbyl; and R¹³ is selected from the group consisting of H and C₁to about C₂₀ hydrocarbyl.
 133. The method of claim 132 in which R¹³ is agroup having the structure of Formula (43)


134. The method of claim 133 wherein R⁷ is a C₁ to about C₁₀hydrocarbyl.
 135. The method of claim 134 wherein R⁷ is a C₁ to about C₅hydrocarbyl.
 136. The method of claim 135 wherein R⁷ is methyl.
 137. Themethod of claim 2 further comprising a sulfone-forming step in which asubstituted diphenyl methane compound having the structure of Formula(11)

is reacted under sulfination conditions and coupled with a 2-substitutedacrolein compound having the structure of Formula (21)

to form a monoalkyl sulfone aldehyde compound having the structure ofFormula (19)

wherein: R¹ is a C₁ to about C₂₀ hydrocarbyl; R⁶ is a protecting group;and X³ is an aromatic substitution leaving group.
 138. A method for thepreparation of a benzylammonium compound having the structure of Formula(1)

wherein the method comprises the steps of: (a) treating a protectedphenol compound having the structure of Formula (14)

 with a substituted benzoyl compound having the structure of Formula(15)

 under acylation conditions to produce a substituted benzophenonecompound having the structure of Formula (13)

(b) reducing the substituted benzophenone compound to produce asubstituted diphenyl methane compound having the structure of Formula(11)

(c) coupling the substituted diphenyl methane compound with asubstituted propionaldehyde compound having the structure of Formula(10)

 in the presence of a source of sulfur to form a nitro sulfide aldehydecompound having the structure of Formula (10)

(d) oxidizing the nitro sulfide aldehyde compound to form a nitrosulfone aldehyde compound having the structure of Formula (9)

(e) reductively alkylating the nitro sulfone aldehyde compound to forman amino sulfone aldehyde compound having the structure of Formula (8)

(f) treating the amino sulfone aldehyde compound under cyclizationconditions to form protected phenol compound having the

(g) deprotecting the protected phenol compound to form a phenol compoundhaving the structure of Formula (4)

(h) coupling the phenol compound with a substituted xylene having thestructure of Formula (5)

 under substitution conditions to produce a benzyl alcohol ethercompound having the structure of Formula (6)

(i) treating the benzyl alcohol ether compound with a leavinggroup-forming reagent to produce a derivatized benzyl ether compoundhaving the structure of Formula (2)

(j) treating the derivatized benzyl ether compound with an amine havingthe structure of Formula (42):

 under amination conditions to produce the benzylammonium compound; wherein: R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl; R³,R⁴, and R⁵ independently are selected from the group consisting of H andC₁ to about C₂₀ hydrocarbyl, wherein optionally one or more carbon atomof the hydrocarbyl is replaced by O, N, or S, and wherein optionally twoor more of R³, R⁴, and R⁵ taken together with the atom to which they areattached form a cyclic structure; R⁶ is a protecting group; X and X⁴independently are nucleophilic leaving groups; X² is selected from thegroup consisting of chloro, bromo, iodo, methanesulfonato,trifluoromethanesulfonato, benzenesulfonato, and toluenesulfonato; X³ isan aromatic substitution leaving group; and X⁵ is selected from thegroup consisting of hydroxy and halo.
 139. The method of claim 138further comprising an enantiomeric enrichment step.
 140. The method ofclaim 139 wherein the benzylammonium compound produced by the methodcomprises a (4R,5R) enantiomer that preponderates over a (4S,5S)enantiomer.
 141. A method for the preparation of a derivatized benzylether compound having the structure of Formula (2).

wherein the method comprises treating a benzyl alcohol ether compoundhaving the structure of Formula (6)

with a halogenating agent to form the derivatized benzyl ether compound,wherein R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl, and Xis halo.
 142. The method of claim 141 wherein the derivatized benzylether compound produced by the method comprises a (4R,5R) enantiomerthat preponderates over a (4S,5S) enantiomer.
 143. A method for thepreparation of a benzyl alcohol ether compound having the structure ofFormula (6)

wherein the method comprises contacting a phenol compound having thestructure of Formula (4)

with a substituted xylene compound having the structure of Formula (5)

under substitution conditions to produce the benzyl alcohol ethercompound, wherein R¹ and R² independently are C₁ to about C₂₀hydrocarbyl, and X² is selected from the group consisting of chloro,bromo, iodo, methanesulfonato, trifluoromethylsuflonato, andtoluenesulfonato.
 144. The method of claim 143 wherein R¹ and R²independently are C₁ to about C₁₀ hydrocarbyl.
 145. The method of claim144 wherein R¹ and R² independently are C₁ to about C₅ hydrocarbyl. 146.The method of claim 145 wherein R¹ and R² are both butyl.
 147. Themethod of claim 145 wherein one of R¹ and R² is ethyl and the other ofR¹ and R² is butyl.
 148. The method of claim 143 wherein the contactingof the phenol compound with the substituted xylene compound is performedin the presence of a solvent.
 149. The method of claim 148 wherein thesolvent comprises a compound selected from the group consisting of anaromatic solvent, an amide, an ester, a ketone, an ether, and asulfoxide.
 150. The method of claim 149 wherein the solvent comprises anamide.
 151. The method of claim 150 wherein the amide is selected fromthe group consisting of dimethylformamide and N,N-dimethylacetamide.152. The method of claim 149 wherein the solvent comprises an aproticsolvent.
 153. The method of claim 143 wherein the contacting of thephenol compound with the substituted xylene compound is performed in thepresence of a base.
 154. The method of claim 153 wherein the basecomprises a compound selected from the group consisting of a metalhydroxide, a metal alcoholate, a metal hydride, an alkyl metal complex,and an amide base.
 155. The method of claim 154 wherein the basecomprises a metal hydroxide.
 156. The method of claim 155 wherein themetal hydroxide is selected from the group consisting of sodiumhydroxide, lithium hydroxide, and calcium hydroxide.
 157. The method ofclaim 156 wherein the metal hydroxide is sodium hydroxide.
 158. Themethod of claim 143 wherein the benzyl alcohol ether compound producedby the method comprises a (4R,5R) enantiomer that preponderates over a(4S,5S) enantiomer.
 159. A method for the preparation of a phenolcompound having the structure of Formula (4)

wherein the method comprises deprotecting a protected phenol compoundhaving the structure of Formula (7)

to form the phenol compound, wherein R¹ and R² independently are C₁ toabout C₂₀ hydrocarbyl, and R⁶ is a protecting group.
 160. The method ofclaim 159 wherein the phenol compound produced by the method comprises a(4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.
 161. Amethod for the preparation of a protected phenol compound having thestructure of Formula (7)

wherein the method comprises cyclizing an amino sulfone aldehydecompound having the structure of Formula (8)

under cyclization conditions to form the protected phenol compound,wherein R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl, and R⁶is a protecting group.
 162. The method of claim 161 wherein theprotected phenol compound produced by the method comprises a (4R,5R)enantiomer that preponderates over a (4S,5S) enantiomer.
 163. A methodfor the preparation of an amino sulfone aldehyde compound having thestructure of Formula (8)

wherein the method comprises reductively alkylating a nitro sulfonealdehyde compound having the structure of Formula (9)

to form the amino sulfone aldehyde compound, wherein R¹ and R²independently are C₁ to about C₂₀ hydrocarbyl, and R⁶ is a protectinggroup.
 164. A method for the preparation of a nitro sulfone aldehydecompound having the structure of Formula (9)

wherein the method comprises oxidizing a nitro sulfide aldehyde compoundhaving the structure of Formula (10)

to form the nitro sulfone aldehyde compound, wherein R¹ and R²independently are C₁ to about C₂₀ hydrocarbyl, and R⁶ is a protectinggroup.
 165. A method for the preparation of a nitro sulfide aldehydehaving the structure of Formula (10)

wherein the method comprises coupling a substituted diphenyl methanecompound having the structure of Formula (11)

with a substituted propionaldehyde compound having the structure ofFormula (12)

in the presence of a source of sulfur to form the nitro sulfidealdehyde, wherein: R¹ and R² independently are C₁ to about C₂₀hydrocarbyl; R⁶ is a protecting group; X³ is an aromatic substitutionleaving group; and X⁴ is a nucleophilic substitution leaving group. 166.A method for the preparation of a substituted diphenyl methane compoundhaving the structure of Formula (11)

wherein the method comprises reducing a substituted benzophenonecompound having the structure of Formula (13)

to form the substituted diphenyl methane compound, wherein: R⁶ is aprotecting group; and X³ is an aromatic substitution leaving group. 167.A method for the preparation of a substituted benzophenone compoundhaving the structure of Formula (13)

wherein the method comprises reacting a protected phenol compound havingthe structure of Formula (14)

with a substituted benzoyl compound having the structure of Formula (15)

under acylation conditions to produce the substituted benzophenonecompound, wherein: R⁶ is a protecting group; X³ is an aromaticsubstitution leaving group; X⁵ is selected from the group consisting ofhydroxy, bromo, iodo, and —OR¹⁴; and R¹⁴ is an acyl group.
 168. Themethod of claim 167 wherein X5 is hydroxy.
 169. The method of claim 168wherein the acylation conditions comprise a strong protic acid.
 170. Themethod of claim 169 wherein the strong protic acid is selected from thegroup consisting of sulfuric acid, a sulfonic acid, or a phosphorus oxyacid.
 171. The method of claim 170 wherein the strong protic acid is aphosphorus oxy acid.
 172. The method of claim 171 wherein the phosphorusoxy acid is selected from the group consisting of orthophosphoric acid,pyrophosphoric acid, and polyphosphoric acid.
 173. The method of claim171 wherein the phosphorus oxy acid comprises polyphosphoric acid. 174.The method of claim 167 wherein R⁶ is a C₁ to about C₁₀ hydrocarbylgroup.
 175. The method of claim 174 wherein R⁶ is a C₁ to about C₁₀alkyl group.
 176. The method of claim 175 wherein R⁶ is a C₁ to about C₅alkyl group.
 177. The method of claim 176 wherein R⁶ is methyl.
 178. Amethod for the preparation of a substituted benzophenone compound havingthe structure of Formula (13)

wherein the method comprises reacting an aryl metal complex having thestructure of Formula (56)

with a substituted benzoyl compound having the structure of Formula (15)

under acylation conditions to produce the substituted benzophenonecompound, wherein: R⁶ is a protecting group; L is a metal-containingmoiety; X³ is an aromatic substitution leaving group; X⁵ is selectedfrom the group consisting of halo and —OR¹⁴; and R¹⁴ is an acyl group.179. The method of claim 178 wherein L is selected from the groupconsisting of MgX⁶, Na, and Li, wherein X⁶ is a halogen.
 180. A methodfor the preparation of an amino sulfone aldehyde compound having thestructure of Formula (17)

wherein the method comprises reducing and reductively alkylating analkenyl sulfone aldehyde compound having the structure of Formula (16)

to form the amino sulfone aldehyde compound wherein R¹ is a C₁ to aboutC₂₀ hydrocarbyl group; R⁶ is a protecting group; and R⁷ is selected fromthe group consisting of H and C1 to about C17 hydrocarbyl.
 181. A methodfor the preparation of an alkenyl sulfone aldehyde compound having thestructure of Formula (16)

wherein the method comprises thermolyzing an acetal compound having thestructure of Formula (18)

to form the alkenyl sulfone aldehyde compound, wherein R¹ is a C₁ toabout C₂₀ hydrocarbyl group; R⁶ is a protecting group; R⁷ is selectedfrom the group consisting of H and C₁ to about C₁₇ hydrocarbyl; and R¹³is selected from the group consisting of H and C₁ to about C₂₀hydrocarbyl.
 182. A method for the preparation of an acetal compoundhaving the structure of Formula (18)

wherein the method comprises reacting a monoalkyl sulfone aldehydecompound having the structure of Formula (19)

with an allyl alcohol having the structure of Formula (20)

optionally in the presence of a hydroxylated solvent having thestructure HOR¹³ to form the acetal compound, wherein: R¹ is a C₁ toabout C₂₀ hydrocarbyl; R⁶ is a protecting group; R⁷ is selected from thegroup consisting of H and a C₁ to about C₁₇ hydrocarbyl; and R¹³ isselected from the group consisting of H and C₁ to about C₂₀ hydrocarbyl.183. The method of claim 182 in which R¹³ is a group having thestructure of Formula (43)


184. The method of claim 183 wherein R⁷ is a C₁ to about C₁₀hydrocarbyl.
 185. The method of claim 184 wherein R⁷ is a C₁ to about C₅hydrocarbyl.
 186. The method of claim 185 wherein R⁷ is methyl.
 187. Amethod for the preparation of a monoalkyl sulfone aldehyde compoundhaving the structure of Formula (19)

wherein the method comprises reacting a substituted diphenyl methanecompound having the structure of Formula (11)

under sulfination conditions to produce a sulfination mixture andcontacting the sulfination mixture with a 2-hydrocarbyl acroleincompound having the structure of Formula (21)

thereby forming the monoalkyl sulfone aldehyde compound, wherein: R¹ isa C to about C₂₀ hydrocarbyl; R⁶ is a protecting group; and X³ is anaromatic substitution leaving group.
 188. A method for the preparationof a 3-sulfur-propionaldehyde olefin compound having the structure ofFormula 49

wherein the method comprises contacting a 3-sulfur-propionaldehydecompound having the structure of Formula 48

with an allyl alcohol compound having the structure of Formula 50

in the presence of a source of acid, thereby forming the3-sulfur-propionaldehyde olefin compound, wherein: R¹⁵ is selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylaryl,arylalkylaryl, and acyl, wherein alkyl, alkenyl, alkynyl, aryl,alkylaryl, arylalkylaryl, and acyl optionally are substituted with atleast one R²² group; R¹⁶, R¹⁷, R^(21a), and R^(21b) are independentlyselected from the group consisting of H and hydrocarbyl; R²² is selectedfrom the group consisting of H, —NO₂, amino, C₁ to about C₁₀alkylamino,di(C₁ to about C₁₀)alkylamino, C₁ to about C₁₀ alkylthio, hydroxy, C₁ toabout C₁₀alkoxy, cyanato, isocyanato, halogen, OR⁶, SR⁶, SR⁶R^(6a), andNR⁶R^(6a); R⁶ and R^(6a) independently are selected from the groupconsisting of H and a protecting group; and q is 0, 1, or
 2. 189. Themethod of claim 188 wherein R¹⁵ is selected from the group consisting ofaryl, alkylaryl, and arylalkylaryl.
 190. The method of claim 188 whereinR¹⁵ is substituted with at least one R²² group.
 191. The method of claim190 wherein R¹⁵ is arylalkylaryl optionally substituted with at leastone R²² group.
 192. The method of claim 189 wherein R¹⁵ is2-(phenylmethyl)phenyl.
 193. The method of claim 192 wherein R¹⁵ issubstituted with at least one R²² group.
 194. The method of claim 188wherein R¹⁶ is hydrocarbyl.
 195. The method of claim 194 wherein R¹⁶ isa C₁ to about C₁₀hydrocarbyl.
 196. The method of claim 195 wherein R¹⁶is a C₁ to about C₅ hydrocarbyl.
 197. The method of claim 196 whereinR¹⁶ is selected from the group consisting of ethyl and butyl.
 198. Themethod of claim 188 wherein R¹⁷ is hydrocarbyl.
 199. The method of claim188 wherein q is
 2. 200. The method of claim 188 wherein the contactingis performed at a temperature of about 0° C. to about 200° C.
 201. Themethod of claim 200 wherein the contacting is performed at a temperatureof about 20° C. to about 150° C.
 202. The method of claim 201 whereinthe contacting is performed at a temperature of about 30° C. to about135° C.
 203. The method of claim 202 wherein the contacting is performedat a temperature of about 30° C. to about 100° C.
 204. The method ofclaim 188 wherein the contacting is performed in the presence of asolvent.
 205. The method of claim 203 further comprising a step in whichthe solvent is azeotropically removed.
 206. A method of treating adiastereomer of a tetrahydrobenzothiepine compound having the structureof Formula (22)

wherein Formula (22) comprises a (4,5)-diastereomer selected from thegroup consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a(4R,5S) diastereomer, and a (4S,5R) diastereomer, to produce a mixturecomprising the (4S,5S) diastereomer and the (4R,5R) diastereomer,wherein the method comprises contacting a base with a feedstockcomposition comprising the diastereomer of the tetrahydrobenzothiepinecompound, thereby producing a mixture of diastereomers of thetetrahydrobenzothiepine compound; and wherein R¹ and R² independentlyare C₁ to about C₂₀ hydrocarbyl; R⁸ is selected from the groupconsisting of H, hydrocarbyl, heterocyclyl, ((hydroxyalkyl)aryl)-alkyl,((cycloalkyl)alkylaryl)alkyl, ((heterocycloalkyl)alkylaryl)alkyl,((quaternary heterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl,wherein hydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl optionally haveone or more carbons replaced by a moiety selected from the groupconsisting of O, NR³, N⁺R³R⁴A⁻, S, SO, SO₂, S⁺R³A⁻, PR³, P⁺R³R⁴A⁻,P(O)R³, phenylene, carbohydrate, amino acid, peptide, and polypeptide,and R⁸ is optionally substituted with one or more moieties selected fromthe group consisting of sulfoalkyl, quaternary heterocycle, quaternaryheteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo,CO₂R³, CN, halogen, CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻,S⁺R³R⁴A⁻, and C(O)OM; R²³ and R²⁴ are independently selected from thesubstituents constituting R³ and M; A⁻ is a pharmaceutically acceptableanion and M is a pharmaceutically acceptable cation; and R⁹ is selectedfrom the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl,heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl,OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo, CO₂R³, CN,halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻,S⁺R³R⁴A⁻, and C(O)OM; R³, R⁴, and R⁵ independently are selected from thegroup consisting of H and C₁ to about C₂₀ hydrocarbyl, whereinoptionally one or more carbon atom of the hydrocarbyl is replaced by O,N, or S, and wherein optionally two or more of R³, R⁴, and R⁵ takentogether with the atom to which they are attached form a cyclicstructure; n is a number from 0 to 4; and x is 1 or
 2. 207. The methodof claim 206 wherein the base is selected from the group consisting ofan alkali metal hydroxide, an alkaline earth metal hydroxide, an alkalimetal alkoxide, a metal hydride, an alkali metal amide, and an alkalimetal hydrocarbyl base.
 208. The method of claim 207 wherein the base isselected from the group consisting of an alkali metal hydroxide, analkaline earth metal hydroxide, an alkali metal alkoxide, and an alkalimetal amide.
 209. The method of claim 208 wherein the base is an alkalimetal alkoxide.
 210. The method of claim 209 wherein the base isselected from the group consisting of a sodium alkoxide and a potassiumalkoxide.
 211. The method of claim 210 wherein the base is potassiumt-butoxide.
 212. The method of claim 206 wherein R⁸ is selected from thegroup consisting of H, C₁ to about C₂₀ alkyl, hydroxyalkylarylalkyl, andheterocycloalkylalkylarylalkyl.
 213. The method of claim 212 wherein R⁸is selected from the group consisting of H, and C₁ to about C₂₀ alkyl.214. The method of claim 213 wherein R⁸ is C₁ to about C₂₀ alkyl. 215.The method of claim 214 wherein R⁸ is C₁ to about C₁₀ alkyl.
 216. Themethod of claim 217 wherein R⁸ is C₁ to about C5 alkyl.
 217. The methodof claim 214 wherein R⁸ is methyl.
 218. The method of claim 206 whereinR⁹ is selected from the group consisting of H, amino, alkylamino,alkoxy, and nitro.
 219. The method of claim 218 wherein R⁹ is selectedfrom the group consisting of H and alkylamino.
 220. The method of claim219 wherein R⁹ is alkylamino.
 221. The method of claim 219 wherein R⁹ isdimethylamino and n is
 1. 222. The method of claim 221 wherein R⁹ is inthe 7-position of the tetrahydrobenzothiepine compound.
 223. The methodof claim 206 wherein one of R¹ and R² is ethyl and the other of R¹ andR² is butyl.
 224. The method of claim 206 wherein are both R¹ and R² arebutyl.
 225. The method of claim 206 wherein the (4,5)-diastereomer isselected from the group consisting of a (4S,5S) diastereomer, a (4R,5S)diastereomer, and a (4S,5R) diastereomer.
 226. The method of claim 225wherein the (4,5)-diastereomer is a (4S,5S) diastereomer.
 227. Themethod of claim 206 wherein the tetrahydrobenzothiepine compound has thestructure of Formula (24)


228. The method of claim 206 wherein the feedstock composition furthercomprises an amino sulfone aldehyde compound having the structure ofFormula (8)

wherein R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl, and R⁶is a protecting group.
 229. The method of claim 228 wherein R¹ and R²independently are C₁ to about C₁₀hydrocarbyl.
 230. The method of claim229 R¹ and R² independently are C₁ to about C₅ hydrocarbyl.
 231. Themethod of claim 230 wherein one of R¹ and R² is ethyl and the other ofR¹ and R² is butyl.
 232. The method of claim 231 wherein both R¹ and R²are butyl.
 233. The method of claim 228 wherein R⁶ is C₁ to about C₁₀hydrocarbyl.
 234. The method of claim 233 wherein R⁶ is methyl.
 235. Amethod of treating a diastereomer of a tetrahydrobenzothiepine compoundhaving the structure of Formula (22)

wherein Formula (22) comprises a (4,5)-diastereomer selected from thegroup consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a(4R,5S) diastereomer, and a (4S,5R) diastereomer, to produce a mixturecomprising the (4S,5S) diastereomer and the (4R,5R) diastereomer,wherein the method comprises treating the diastereomer of thetetrahydrobenzothiepine compound under elimination conditions to producea dihydrobenzothiepine compound having the structure of Formula (23)

 and oxidizing the dihydrobenzothiepine compound thereby producing themixture comprising the (4S,5S) diastereomer and the (4R,5R)diastereomer, wherein R¹ and R² independently are C₁ to about C₂₀hydrocarbyl; R⁸ is selected from the group consisting of H, hydrocarbyl,heterocyclyl, ((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl,((heterocycloalkyl)alkylaryl)alkyl, ((quaternaryheterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl, whereinhydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle, quaternaryheteroaryl, and quaternary heteroarylalkyl optionally have one or morecarbons replaced by a moiety selected from the group consisting of O,NR³, N⁺R³R⁴A⁻, S, SO, SO₂, S⁺R³A⁻, PR³, P⁺R³R⁴A⁻, P(O)R³, phenylene,carbohydrate, amino acid, peptide, and polypeptide, and R⁸ is optionallysubstituted with one or more moieties selected from the group consistingof sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR³,NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo, CO₂R³, CN, halogen,CONR³R⁴, SO₂OM, SO₂NR R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, andC(O)OM; R³, R⁴, and R⁵ independently are selected from the groupconsisting of H and C₁ to about C₂₀ hydrocarbyl, wherein optionally oneor more carbon atom of the hydrocarbyl is replaced by O, N, or S, andwherein optionally two or more of R³, R⁴, and R⁵ taken together with theatom to which they are attached form a cyclic structure; R²³ and R²⁴ areindependently selected from the substituents constituting R³ and M; A⁻is a pharmaceutically acceptable anion and M is a pharmaceuticallyacceptable cation; and R⁹ is selected from the group consisting of H,hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl,ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³,SO₂R³, SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, S₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³, R⁴A⁻, and C(O)OM; n is a number from 0to 4; X⁷ is selected from the group consisting of S, NH, and O; and x is0, 1, or
 2. 236. The method of claim 235 wherein the eliminationconditions comprise an acid.
 237. The method of claim 235 wherein theelimination conditions comprise a base.
 238. The method of claim 235wherein the elimination conditions comprise derivatizing thediastereomer of a tetrahydrobenzothiepine compound to form atetrahydrobenzothiepine derivative having an elimination-labile group atthe 4-position, and eliminating the elimination-labile group to form thedihydrobenzothiepine compound.
 239. The method of claim 235 wherein theoxidation step comprises an alcohol-forming step in which thedihydrobenzothiepine compound is reacted under alcohol-formingconditions to produce a mixture of diastereomers of thetetrahydrobenzothiepine compound.
 240. The method of claim 235 whereinthe (4,5)-diastereomer is selected from the group consisting of a(4S,5S) diastereomer, a (4R,5S) diastereomer, and a (4S,5R)diastereomer.
 241. The method of claim 240 wherein the(4,5)-diastereomer is a (4S,5S) diastereomer.
 242. The method of claim235 wherein the tetrahydrobenzothiepine compound has the structure ofFormula (24)

and the dihydrobenzothiepine compound has the structure of Formula (25)


243. A compound having the structure of Formula (2)

wherein R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl and X isselected from the group consisting of Br, I, and a nucleophilicsubstitution leaving group covalently bonded to the compound via anoxygen atom.
 244. The compound of claim 243 wherein R¹ and R²independently are C₁ to about C₁₀ hydrocarbyl.
 245. The compound ofclaim 244 wherein R¹ and R² independently are C₁ to about C₅hydrocarbyl.
 246. The compound of claim 245 wherein one of R¹ and R² isethyl and the other of R¹ and R² is butyl.
 247. The compound of claim245 wherein R¹ and R² are both butyl.
 248. The compound of claim 243wherein X is selected from the group consisting of Br, I, and hydroxy.249. The compound of claim 248 wherein X is selected from the groupconsisting of Br and I.
 250. The compound of claim 249 wherein X ischloro.
 251. The compound of claim 248 wherein X is hydroxy.
 252. Thecompound of claim 243 having the structure of Formula (26)


253. The compound of claim 252 having a (4R,5R) absolute configuration.254. The compound of claim 243 having the structure of Formula (27)


255. The compound of claim 254 having a (4R,5R) absolute configuration.256. A compound having the structure of Formula (28)


257. The compound of claim 256 having a (4R,5R) absolute configuration.258. A compound having the structure of Formula (24)

wherein Formula (22) represents a (4,5)-diastereomer selected from thegroup consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a(4R,5S) diastereomer, and a (4S,5R) diastereomer.
 259. The compound ofclaim 258 wherein the (4,5)-diastereomer is a (4R,5R) diastereomer. 260.A compound having the structure of Formula (29)


261. A compound having the structure of Formula (30)


262. 2-Bromomethyl-2-butylhexanal.
 263. 2-Bromomethyl-2-butylhexanol.264. 1-Acetato-2-butyl-2-(hydroxymethyl)hexane.
 265. A compound havingthe structure of Formula (31)

wherein Formula (31) represents a compound having either an E or a Zconfiguration about the butenyl double bond.
 266. The compound of claim265 having an E configuration about the butenyl double bond.
 267. Thecompound of claim 265 having a Z configuration about the butenyl doublebond.
 268. A compound having the structure of Formula (32)


269. A compound having the structure of Formula (32)

wherein R⁶ is a protecting group and X³ is an aromatic substitutionleaving group.
 270. The compound of claim 269 wherein X³ is a halogroup.
 271. The compound of claim 270 wherein X³ is chloro.
 272. Thecompound of claim 269 wherein R⁶ is C₁ to about C₂₀ alkyl.
 273. Thecompound of claim 272 wherein R⁶ is C₁ to about C₁₀alkyl.
 274. Thecompound of claim 273 wherein R⁶ is C₁ to about Cs alkyl.
 275. Thecompound of claim 274 wherein R⁶ is methyl.
 276. A compound having thestructure of Formula (13)

wherein R⁶ is a protecting group and X³ is an aromatic substitutionleaving group.
 277. The compound of claim 276 wherein X³ is a halogroup.
 278. The compound of claim 277 wherein X³ is chloro.
 279. Thecompound of claim 276 wherein R⁶ is C₁ to about C₂₀ alkyl.
 280. Thecompound of claim 279 wherein R⁶ is C₁ to about C₁₀ alkyl.
 281. Thecompound of claim 280 wherein R⁶ is C₁ to about C₅ alkyl.
 282. Thecompound of claim 281 wherein R⁶ is methyl.
 283. A method for thepreparation of a substituted propionaldehyde compound having thestructure of Formula 12

wherein the method comprises oxidizing a substituted propanol compoundhaving the structure of Formula 35

wherein R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl and X⁴is a nucleophilic substitution leaving group.
 284. The method of claim283 wherein one of R¹ and R² is ethyl and the other of R¹ and R² isbutyl.
 285. The method of claim 284 wherein the substitutedpropionaldehyde compound has an R absolute configuration.
 286. Themethod of claim 284 wherein the substituted propionaldehyde compound hasan S absolute configuration.
 287. The method of claim 283 wherein R¹ andR² are both butyl.
 288. The method of claim 283 further comprising astep in which an acid ester having the structure of Formula 36

is solvolyzed to form the substituted propanol compound, wherein R¹⁰ isa C₁ to about C₂₀ alkyl group.
 289. The method of claim 283 wherein X⁴is halo.
 290. The method of claim 289 wherein X⁴ is bromo.
 291. Themethod of claim 289 further comprising a step in which a diol compoundhaving the structure of Formula 37

is reacted in the presence of carbonyl compound having the structure ofFormula 38

and a source of halide to form the acid ester, wherein X⁶ is selectedfrom the group consisting of hydroxy, halogen, and —OC(O)R¹⁸, whereinR¹⁸ is C₁ to about C₂₀ hydrocarbyl.
 292. The method of claim 291 whereinthe source of halide is selected from the group consisting of a sourceof HBr and a source of HI.
 293. The method of claim 292 wherein thesource of halide is a source of HBr.
 294. A method for the preparationof a substituted propionaldehyde compound having the structure ofFormula 12

wherein the method comprises the steps of: (a) reacting a diol compoundhaving the structure of Formula 37

 in the presence of a carbonyl compound having the structure of Formula38

 and a source of halide to form an acid ester having the structure ofFormula 36

(b) solvolyzing the acid ester to form a substituted propanol compoundhaving the structure of Formula 35

(c) oxidizing the substituted propanol compound to form the substitutedpropionaldehyde compound;  wherein: R¹, R², R¹⁰, and R¹⁸ independentlyare C₁ to about C₂₀ hydrocarbyl; X⁴ is a nucleophilic substitutionleaving group; and X⁶ is selected from the group consisting of hydroxy,halo, and —OC(O)R¹⁸.
 295. The method of claim 294 wherein the carboxylicacid equivalent is a carbonyl compound having the structure of Formula38

wherein X⁶ is selected from the group consisting of hydroxy, halo, and—OC(O)R¹⁸.
 296. The method of claim 295 wherein R¹, R², R¹⁰, and R¹¹independently are C₁ to about C₁₀ hydrocarbyl.
 297. The method of claim296 wherein R¹, R², R¹⁰, and R¹⁸ independently are C₁ to about C₅hydrocarbyl.
 298. The method of claim 297 wherein one of R¹ and R² isethyl and the other of R¹ and R² is butyl.
 299. The method of claim 297wherein both R¹ and R² are butyl.
 300. The method of claim 299 whereinR¹⁰ is methyl.
 301. The method of claim 297 wherein R¹⁸ is methyl. 302.The method of claim 301 wherein X⁴ is halo.
 303. The method of claim 302wherein X⁴ is bromo.
 304. The method of claim 303 wherein X⁶ is hydroxy.305. A crystalline form of a tetrahydrobenzothiepine compound having thestructure of Formula 71

or an enantiomer thereof wherein the crystalline form has a meltingpoint or a decomposition point of about 278° C. to about 285° C. 306.The crystalline form of claim 305 wherein the tetrahydrobenzothiepinecompound has an absolute configuration predominantly of (4R,5R). 307.The crystalline form of claim 305 having a melting point or adecomposition point of about 280° C. to about 283° C.
 308. Thecrystalline form of claim 307 having a melting point or a decompositionpoint of about 282° C.
 309. The crystalline form of claim 305 having anX-ray powder diffraction pattern with peaks at about 9.2 degrees 2theta, about 12.3 degrees 2 theta, and about 13.9 degrees 2 theta. 310.The crystalline form of claim 309 wherein the X-ray powder diffractionpattern substantially lacks peaks at about 7.2 degrees 2 theta and atabout 11.2 degrees 2 theta.
 311. The crystalline form of claim 305having an X-ray powder diffraction pattern substantially as shown inplot (b) of FIG.
 6. 312. The crystalline form of claim 305 having an IRspectrum with a peak at 10 about 3245 cm⁻¹ to about 3255 cm⁻¹.
 313. Thecrystalline form of claim 312 having an IR spectrum with a peak at about1600 cm⁻¹.
 314. The crystalline form of claim 312 having an IR spectrumwith a peak at about 1288 cm⁻¹.
 315. The crystalline form of claim 312having an IR spectrum substantially as shown in plot (b) of FIG.
 7. 316.The crystalline form of claim 305 having a solid state carbon-13 NMRspectrum with peaks at about 142.3 ppm, about 137.2 ppm, and about 125.4ppm.
 317. The crystalline form of claim 305 having a solid statecarbon-13 NMR spectrum substantially as shown in plot (b) of FIG. 8.318. The crystalline form of claim 305 that after an essentially drysample of the crystalline form is equilibrated under about 80% relativehumidity air at 25° C. gains less than 1% of its own weight.
 319. Thecrystalline form of claim 305 that is essentially nonhygroscopic.
 320. Acrystalline form of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71

and that after a sample of the crystalline form is dried at essentially0% relative humidity at about 25° C. under a purge of essentially drynitrogen until the sample exhibits essentially no weight change as afunction of time, the sample gains less than 1% of its own weight whenequilibrated under about 80% relative humidity air at about 25° C. 321.A crystalline form of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71

and wherein the crystalline form is produced by crystallizing thetetrahydrobenzothiepine compound from a solvent comprising methyl ethylketone.
 322. A method for the preparation of a crystalline form of atetrahydrobenzothiepine compound having the structure of Formula 63

wherein the method comprises crystallizing the tetrahydrobenzothiepinecompound from a solvent comprising methyl ethyl ketone, and wherein: R¹and R² independently are C₁ to about C₂₀ hydrocarbyl; R³, R⁴, and R⁵independently are selected from the group consisting of H and C₁ toabout C₂₀ hydrocarbyl, wherein optionally one or more carbon atom of thehydrocarbyl is replaced by O, N, or S, and wherein optionally two ormore of R³, R⁴, and R⁵ taken together with the atom to which they areattached form a cyclic structure; R⁹ is selected from the groupconsisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl,heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR³, NR³R⁴,N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo, CO₂R³, CN, halogen, NCO,CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, andC(O)OM; R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M; n is a number from 0 to 4; A⁻ and Z⁻independently are pharmaceutically acceptable anions; and M is apharmaceutically acceptable cation.
 323. The method of claim 322 whereinthe tetrahydrobenzothiepine compound has the structure of Formula 64


324. The method of claim 323 wherein the tetrahydrobenzothiepinecompound has the structure of Formula 41


325. A method for the preparation of a product crystal form of atetrahydrobenzothiepine compound having the compound structure ofFormula 41

wherein the product crystal form has a melting point or a decompositionpoint of about 278° C. to about 285° C., wherein the method comprisesapplying heat to an initial crystal form of the tetrahydrobenzothiepinecompound wherein the initial crystal form has a melting point or adecomposition point of about 220° C. to about 235° C., thereby formingthe product crystal form.
 326. The method of claim 325 wherein theinitial crystal form is heated to a temperature from about 20° C. toabout 150° C.
 327. The method of claim 326 wherein the initial crystalform is heated to a temperature from about 50° C. to about 125° C. 328.The method of claim 327 wherein the initial crystal form is heated to atemperature from about 60° C. to about 100° C.
 329. The method of claim325 wherein the method further comprises a cooling step after the stepin which the initial crystal form is heated.
 330. The method of claim325 further comprising mixing the initial crystal form with a solvent.331. The method of claim 330 wherein the solvent comprises a ketone.332. The method of claim 331 wherein the ketone is selected from thegroup consisting of methyl ethyl ketone, acetone, and methyl isobutylketone.
 333. The method of claim 332 wherein the ketone is methyl ethylketone.
 334. The method of claim 332 wherein the ketone is acetone. 335.The method of claim 332 wherein the ketone is methyl isobutyl ketone.336. The method of claim 330 wherein the method further comprises acooling step after the step in which the initial crystal form is heated.